Agonists of beta-adrenoceptors

ABSTRACT

The present invention relates to novel compounds of formula (I), to a process for their manufacture, to pharmaceutical compositions containing them, and to their use in therapy, in particular their use in the prophylaxis and treatment of respiratory diseases.

This application is filed under 35 U.S.C. § 371 as the U.S. NationalPhase Application of International Application No. PCT/EP02/02317 filedMar. 4, 2002 claiming priority from Great Britain Application Nos.0105740.5 and 0126994.3 filed Mar. 8, 2001 and Nov. 9, 2001, thedisclosures of which are incorporated herein by reference in theirentirety.

The present invention is concerned with phenethanolamine derivatives,processes for their preparation, compositions containing them and theiruse in medicine, particularly in the prophylaxis and treatment ofrespiratory diseases.

Certain phenethanolamine compounds are known in the art as havingselective stimulant action at β₂-adrenoreceptors and therefore havingutility in the treatment of bronchial asthma and related disorders. ThusGB 2 140 800 describes phenethanolamine compounds including4-hydroxy-a¹-[[[6-(4phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol1-hydroxy-2-naphthalenecarboxylate (salmeterol xinafoate) which is nowused clinically in the treatment of such medical conditions.

Although salmeterol and the other commercially availableβ₂-adrenoreceptor agonists are effective bronchodilators, the maximumduration of action is 12 hours, hence twice daily dosing is oftenrequired. There is therefore a clinical need for compounds having potentand selective stimulant action at β₂-adrenoreceptors and having anadvantageous profile of action.

According to the present invention, there is provided a compound offormula (I)

or a salt, solvate, or physiologically functional derivative thereof,wherein:

-   -   m is an integer of from 2 to 8;    -   n is an integer of from 3 to 11, preferably from 3 to 7;    -   with the proviso that m+n is 5 to 19, preferably 5 to 12;

-   R¹ is —X—R⁶; wherein

-   X is selected from —(CH₂)_(p)— and C₂₋₆alkenylene;

-   R⁶ is selected from

-   R⁷ and R^(7a) are independently selected from hydrogen, C₁₋₆alkyl,    C₃₋₇cycloalkyl, C(O)R^(7b), C(O)NHR^(7b), phenyl, naphthyl, hetaryl,    and phenyl(C₁₋₄alkyl)-, and R⁷ and R^(7a) are optionally substituted    by 1 or 2 groups independently selected from halo, C₁₋₆alkyl,    C₁₋₆alkoxy, C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl), —SO₂(C₁₋₆alkyl),    —SO₂(phenyl), —CO₂H, and —CO₂(C₁₋₄alkyl);-   R^(7b) is selected from hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, phenyl,    naphthyl, hetaryl, and phenyl(C₁₋₄alkyl), and R^(7b) is optionally    substituted by 1 or 2 groups independently selected from halo,    C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl),    —SO₂(C₁₋₆alkyl), —SO₂(phenyl), —CO₂H, and —CO₂(C₁₋₄alkyl);-   R⁸, R^(8a), R⁹ and R^(9a) are independently selected from hydrogen,    C₁₋₆alkyl, C₃₋₇cycloalkyl, phenyl, naphthyl, hetaryl,    phenyl(C₁₋₄alkyl)-, —NR^(10a)SO₂R¹⁰, —NR^(10a)C(O)NR¹⁰R¹¹,    —SO₂NR¹⁰R¹¹, and C₁₋₆alkyl substituted by —CO₂R¹⁰ or —C(O)NR¹⁰, R¹¹;-   R¹⁰, R^(10a) and R¹¹ are independently selected from hydrogen,    C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, and phenyl (C₁₋₄alkyl)-;-   p is an integer from 0 to 6, preferably from 0 to 4:-   R² is selected from hydrogen, C₁₋₆alkyl, C₁₋₆alkoxy, phenyl, halo,    and C₁₋₆haloalkyl;-   R³ is selected from hydrogen, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy,    phenyl, halo, C₁₋₆haloalkyl, —NR⁷CONR⁷R^(7a) and —SO₂NR^(a)R^(b);    -   wherein R^(a) and R^(b) are independently selected from        hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, and phenyl        (C₁₋₄alkyl), or R^(a) and R^(b), together with the nitrogen to        which they are bonded, form a 5-, 6-, or 7-membered nitrogen        containing ring;    -   and R^(a) and R^(b) are each optionally substituted by one or        two groups selected from halo, C₁₋₆alkyl, and C₁₋₆haloalkyl; and-   R⁴ and R⁵ are independently selected from hydrogen and C₁₋₄alkyl    with the proviso that the total number of carbon atoms in R⁴ and R⁵    is not more than 4.

In the definition of X, the term alkenylene includes both cis and transstructures. Examples of suitable alkenylene groups include —CH═CH—.

In the definition of R³, where R^(a) and R^(b) together with thenitrogen atom to which they are bonded form a 5-, 6- or 7-memberednitrogen containing ring the term “5-, 6-, or 7-membered nitrogencontaining ring” means a 5-, 6-, or 7-membered saturated or unsaturatedring which includes the sulphonamide nitrogen atom and optionally 1 or 2other heteroatoms independently selected from nitrogen, sulphur, andoxygen. Suitable examples of such a ring include piperidinyl,morpholinyl, and piperazinyl.

In the definition of R⁷, the term “hetaryl” means a 5- or 6-memberedheteroaromatic ring, such as thienyl, pyridyl or imidazolyl.

In the compounds of formula (I) R² and R³ preferably each representhydrogen.

In the compounds of formula (I), R⁴ and R⁵ are preferably independentlyselected from hydrogen and methyl, more preferably R⁴ and R⁵ are bothhydrogen.

In the compounds of formula (I), m is suitably 3, 4, 5 or 6 and n issuitably 3, 4, 5 or 6. Preferably m is 5 and preferably n is 4 or 5,such that m+n is 8, 9 or 10, preferably 9.

According to a preferred aspect of the invention, there is provided acompound of formula (Ia)

or a salt, solvate, or physiologically functional derivative thereof,wherein R¹ is as defined above for formula (I).

According to a further preferred aspect of the invention, there isprovided a compound of formula (Ib)

or a salt, solvate, or physiologically functional derivative thereof,wherein R¹ is as defined above for formula (I).

According to a yet further preferred aspect of the invention, there isprovided a compound or formula (Ic):

or a salt, solvate, or physiologically functional derivative thereof,wherein R¹ is a defined above for formula (I).

Compounds or formulae (Ia) and (Ic) are particularly preferred.

In the compounds of formulae (I), (Ia), (Ib) and (Ic) the group R¹ ispreferably attached to the meta-position relative to the —O—(CH₂)_(n)—,—O—(CH₂)₄—, —O—(CH₂)₃— or —O—(CH₂)₅ link respectively.

In the compounds of formulae (I), (Ia), (Ib) and (Ic) the group R⁶ ispreferably linked to the moiety X or directly to the phenyl ring via oneof the ring nitrogen atoms of the group R⁶. Advantageously the group R⁶is selected from the groups (a), (b), (d) and (f).

In the compounds of formulae (I), (Ia), (Ib) and (Ic), R⁷, R^(7a), R⁸,R^(8a), R⁹ and R^(9a) are preferably all hydrogen.

Particularly preferred are compounds wherein R⁶ is selected from thegroups (a), (b), (d) and (f) and R⁷, R^(7a), R⁸ and R⁹ are all hydrogen.

Also particularly preferred are compounds wherein R⁶ is a group (a) andR⁸ represents —NHCONH₂ and compounds wherein R⁶ is a group (b) and R⁷represents —CH₂CONH₂.

It is to be understood that the present invention covers allcombinations of particular and preferred groups described hereinabove.

The compounds of formulae (I), (Ia), (Ib) and (Ic) include an asymmetriccentre, namely the carbon atom of the

group. The present invention includes both (S) and (R) enantiomerseither in substantially pure form or admixed in any proportions.Preferably, the compounds of the invention are in the form of the (R)enantiomers.

Similarly, where R⁴ and R⁵ are different groups, the carbon atom towhich they are attached is an asymmetric centre and the presentinvention includes both (S) and (R) enantiomers at this centre either insubstantially pure form or admixed in any proportions.

Thus the compounds of formulae (I), (Ia), (Ib) and (Ic) include allenantiomers and diastereoisomers as well as mixtures thereof in anyproportions.

Preferred compounds of the invention include:

-   3-[3-(4-{[6-([2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(3-{[7-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}propyl)phenyl]imidazolidine-2,4-dione;-   1-[3-(4-{[6-({2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl]amino)hexyl]oxy}butyl)phenyl]imidazolidine-2-one;-   1-[3-(4-{[6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(4-{[6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(4-{[6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(4-{[6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(4-{[6-({(2S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[4-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[2-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]imidazolidine-2,4-dione;-   3-[3-(5-{[5-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}pentyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(5-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}pentyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(6-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}hexyl)phenyl]imidazolidine-2,4-dione;-   (5R)-5-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-5-methylimidazolidine-2,4-dione;-   (5S)-5-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-5-methylimidazolidine-2,4-dione;-   2-{3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,4-dioxoimidazolidin-1-yl}acetamide;-   5-[4-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]imidazolidine-2,4-dione;-   1-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-1,3-dihydro-2H-imidazol    1-2-one;-   3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-5,5-dimethylimidazolidine-2,4-dione;-   3-[3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)phenyl]-1-(methylsulfonyl)imidazolidine-2,4-dione;-   1-[3-(3-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}propyl)phenyl]imidazolidine-2,4-dione;-   N-{1-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-2,5-dioxoimidazolidin-4-yl)urea;-   3-benzyl-1-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   1-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-3-methylimidazolidine-2,4-dione;-   {3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,5-dioxoimidazolidin-1-yl};-   2-{3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,5-dioxoimidazolidin-1-yl}acetamide;-   1-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]imidazolidine-2,4-dione;-   1-Benzyl-3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-1-(methylsulfonyl)imidazolidine-2,4-dione;    and-   4-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-1,2,4-triazolidine-3,5-dione;-   and salts, solvates, and physiologically functional derivatives    thereof.

Particularly preferred compounds of the invention include:

-   3-[3-(4-{[6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(4-{[6-([(2S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   3-[3-(4-{[6-([(2R/S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;-   2-{3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,5-dioxoimidazolidin-1-yl}acetamide    acetate;-   N-{1-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-2,5-dioxoimidazolidin-4-yl}urea    acetate;-   3-[3-(5-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}pentyl)phenyl]imidazolidine-2,4-dione    acetate;    and salts, solvates, and physiologically functional derivatives    thereof.

Especially preferred is3-[3-(4-{[6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneand salts, solvates, and physiologically functional derivatives thereof.

Salts and solvates of compounds of formulae (I), (Ia), (Ib) and (Ic)which are suitable for use in medicine are those wherein the counterionor associated solvent is pharmaceutically acceptable. However, salts andsolvates having non-pharmaceutically acceptable counterions orassociated solvents are within the scope of the present invention, forexample, for use as intermediates in the preparation of other compoundsof formulae (I), (Ia), (Ib) and (Ic) and their pharmaceuticallyacceptable salts, solvates, and physiologically functional derivatives.

By the term “physiologically functional derivative” is meant a chemicalderivative of a compound of formula (I), (Ia), (Ib) or (Ic) having thesame physiological function as the free compound of formula (I), (Ia)(Ib) and (Ic), for example, by being convertible in the body thereto.According to the present invention, examples of physiologicallyfunctional derivatives include esters.

Suitable salts according to the invention include those formed with bothorganic and inorganic acids or bases. Pharmaceutically acceptable acidaddition salts include those formed from hydrochloric, hydrobromic,sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic,trifluoroacetic, triphenylacetic, sulphamic, sulphanilic, succinic,oxalic, fumaric, maleic, malic, glutamic, aspartic, oxaloacetic,methanesulphonic, ethanesulphonic, arylsulphonic (for examplep-toluenesulphonic, benzenesulphonic, naphthalenesulphonic ornaphthalenedisulphonic), salicylic, glutaric, gluconic, tricarballylic,cinnamic, substituted cinnamic (for example, phenyl, methyl , methoxy orhalo substituted cinnamic, including 4-methyl and 4-methoxycinnamicacid), ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or3-hydroxy-2-naphthoic), naphthaleneacrylic (for examplenaphthalene-2-acrylic), benzoic, 4-methoxybenzoic, 2- or4-hydroxybenzoic, 4-chlorobenzoic, 4-phenylbenzoic, benzeneacrylic (forexample 1,4-benzenediacrylic) and isethionic acids. Pharmaceuticallyacceptable base salts include ammonium salts, alkali metal salts such asthose of sodium and potassium, alkaline earth metal salts such as thoseof calcium and magnesium and salts with organic bases such asdicyclohexyl amine and N-methyl-D-glucamine.

Pharmaceutically acceptable esters of the compounds of formula (I),(Ia), (Ib) and (Ic) may have a hydroxyl group converted to a C₁₋₆alkyl,aryl, aryl C₁₋₆ alkyl, or amino acid ester.

As mentioned above, the compounds of formulae (I), (Ia), (Ib) and (Ic)are selective β₂-adrenoreceptor agonists as demonstrated usingfunctional or reporter gene readout from cell lines transfected withhuman beta-adrenoreceptors as described below. Compounds according tothe present invention also have the potential to combine long durationof effect with rapid onset of action. Furthermore, certain compoundshave shown an improved therapeutic index in animal models relative toexisting long-acting β₂-agonist bronchodilators. As such, compounds ofthe invention may be suitable for once-daily administration.

Therefore, compounds of formulae (I), (Ia), (Ib) and (Ic) and theirpharmaceutically acceptable salts, solvates, and physiologicallyfunctional derivatives have use in the prophylaxis and treatment ofclinical conditions for which a selective β₂-adrenoreceptor agonist isindicated. Such conditions include diseases associated with reversibleairways obstruction such as asthma, chronic obstructive pulmonarydiseases (COPD) (e.g. chronic and wheezy bronchitis, emphysema),respiratory tract infection and upper respiratory tract disease.

Other conditions which may be treated include premature labour,depression, congestive heart failure, skin diseases (e.g. inflammatory,allergic, psoriatic, and proliferative skin diseases), conditions wherelowering peptic acidity is desirable (e.g. peptic and gastriculceration) and muscle wasting disease.

Accordingly, the present invention provides a method for the prophylaxisor treatment of a clinical condition in a mammal, such as a human, forwhich a selective β₂-adrenoreceptor agonist is indicated, whichcomprises administration of a therapeutically effective amount of acompound of formula (I), (Ia), (Ib) and (Ic), or a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof. In particular, the present invention provides such a method forthe prophylaxis or treatment of a disease associated with reversibleairways obstruction such as asthma, chronic obstructive pulmonarydisease (COPD), respiratory tract infection or upper respiratory tractdisease. In a further aspect the present invention provides such amethod for the prophylaxis or treatment of a clinical condition selectedfrom premature labour, depression, congestive heart failure, skindiseases (e.g. inflammatory, allergic, psoriatic, and proliferative skindiseases), conditions where lowering peptic acidity is desirable (e.g.peptic and gastric ulceration) or muscle wasting disease.

In the alternative, there is also provided a compound of formula (I),(Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof for use in medicaltherapy, particularly, for use in the prophylaxis or treatment of aclinical condition in a mammal, such as a human, for which a selectiveβ₂-adrenoreceptor agonist is indicated. In particular, there is provideda compound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof for the prophylaxis or treatment of a disease associated withreversible airways obstruction such as asthma, chronic obstructivepulmonary disease (COPD), respiratory tract infection or upperrespiratory tract disease. In a further aspect, there is provided acompound of formula (I), (Ia), (Ib) or (Ic) or a pharmaceuticallyacceptable salt, solvate, or physiologically functional derivativethereof for the prophylaxis or treatment of a clinical conditionselected from premature labour, depression, congestive heart failure,skin diseases (e.g. inflammatory, allergic, psoriatic, and proliferativeskin diseases), conditions where lowering peptic acidity is desirable(e.g. peptic and gastric ulceration) or muscle wasting disease.

The present invention also provides the use of a compound of formula(I), (Ia), (Ib) or (Ic) or a pharmaceutically acceptable salt, solvate,or physiologically functional derivative thereof in the manufacture of amedicament for the prophylaxis or treatment of a clinical condition forwhich a selective β₂-adrenoreceptor agonist is indicated, for example adisease associated with reversible airways obstruction such as asthma,chronic obstructive pulmonary disease (COPD), respiratory tractinfection or upper respiratory tract disease. In a further aspect, thereis provided a compound of formula (I), (Ia), (Ib) or (Ic), or apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof in the manufacture of a medicament for theprophylaxis or treatment of a clinical condition selected from prematurelabour, depression, congestive heart failure, skin diseases (e.g.inflammatory, allergic, psoriatic, and proliferative skin diseases),conditions where lowering peptic acidity is desirable (e.g. peptic andgastric ulceration) and muscle wasting disease.

The amount of a compound of formula (I), (Ia), (Ib) or (Ic), or apharmaceutically acceptable salt, solvate or physiologically functionalderivative thereof which is required to achieve a therapeutic effectwill, of course, vary with the particular compound, the route ofadministration, the subject under treatment, and the particular disorderor disease being treated. The compounds of the invention may beadministered by inhalation at a dose of from 0.0005 mg to 10 mg,preferably 0.005 mg to 0.5 mg. The dose range for adult humans isgenerally from 0.0005 mg to 100mg per day and preferably 0.01 mg to 1 mgper day.

While it is possible for the compound of formula (I), (Ia), (Ib) or(Ic), or a pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof to be administered alone, it is preferableto present it as a pharmaceutical formulation.

Accordingly, the present invention further provides a pharmaceuticalformulation comprising a compound of formula (I), (Ia), (Ib) or (Ic) ora pharmaceutically acceptable salt, solvate, or physiologicallyfunctional derivative thereof, and a pharmaceutically acceptable carrieror excipient, and optionally one or more other therapeutic ingredients.

Hereinafter, the term “active ingredient” means a compound of formula(I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt, solvate,or physiologically functional derivative thereof.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous andintraarticular), inhalation (including fine particle dusts or mistswhich may be generated by means of various types of metered dosepressurised aerosols, nebulisers or insufflators), rectal and topical(including dermal, buccal, sublingual and intraocular) administrationalthough the most suitable route may depend upon for example thecondition and disorder of the recipient. The formulations mayconveniently be presented in unit dosage form and may be prepared by anyof the methods well known in the art of pharmacy. All methods includethe step of bringing the active ingredient into association with thecarrier which constitutes one or more accessory ingredients. In generalthe formulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous liquidor a non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Moulded tablets may be made by moulding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

Formulations for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example saline or water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine, or blisters of for example laminated aluminium foil, for usein an inhaler or insufflator. Formulations generally contain a powdermix for inhalation of the compound of the invention and a suitablepowder base (carrier substance) such as lactose or starch. Use oflactose is preferred. Each capsule or cartridge may generally containbetween 20 μg–10 mg of the compound of formula (I) optionally incombination with another therapeutically active ingredient.Alternatively, the compound of the invention may be presented withoutexcipients. Packaging of the formulation may be suitable for unit doseor multi-dose delivery. In the case of multi-dose delivery, theformulation can be pre-metered (eg as in Diskus, see GB 2242134 orDiskhaler, see GB 2178965, 2129691 and 2169265) or metered in use (eg asin Turbuhaler, see EP 69715). An example of a unit-dose device isRotahaler (see GB 2064336). The Diskus inhalation device comprises anelongate strip formed from a base sheet having a plurality of recessesspaced along its length and a lid sheet hermetically but peelably sealedthereto to define a plurality of containers, each container havingtherein an inhalable formulation containing a compound of formula (I)preferably combined with lactose. Preferably, the strip is sufficientlyflexible to be wound into a roll. The lid sheet and base sheet willpreferably have leading end portions which are not sealed to one anotherand at least one of the said leading end portions is constructed to beattached to a winding means. Also, preferably the hermetic seal betweenthe base and lid sheets extends over their whole width. The lid sheetmay preferably be peeled from the base sheet in a longitudinal directionfrom a first end of the said base sheet.

Spray compositions for topical delivery to the lung by inhalation mayfor example be formulated as aqueous solutions or suspensions or asaerosols delivered from pressurised packs, such as a metered doseinhaler, with the use of a suitable liquefied propellant. Aerosolcompositions suitable for inhalation can be either a suspension or asolution and generally contain the compound of formula (I) optionally incombination with another therapeutically active ingredient and asuitable propellant such as a fluorocarbon or hydrogen-containingchlorofluorocarbon or mixtures thereof, particularly hydrofluoroalkanes,e.g. dichlorodifluoromethane, trichlorofluoromethane,dichlorotetra-fluoroethane, especially 1,1,1,2-tetrafluoroethane,1,1,1,2,3,3,3-heptafluoro-n-propane or a mixture thereof. Carbon dioxideor other suitable gas may also be used as propellant. The aerosolcomposition may be excipient free or may optionally contain additionalformulation excipients well known in the art such as surfactants egoleic acid or lecithin and cosolvents eg ethanol. Pressurisedformulations will generally be retained in a canister (eg an aluminiumcanister) closed with a valve (eg a metering valve) and fitted into anactuator provided with a mouthpiece.

Medicaments for administration by inhalation desirably have a controlledparticle size. The optimum particle size for inhalation into thebronchial system is usually 1–10 μm, preferably 2–5 μm. Particles havinga size above 20 μm are generally too large when inhaled to reach thesmall airways. To achieve these particle sizes the particles of theactive ingredient as produced may be size reduced by conventional meanseg by micronisation. The desired fraction may be separated out by airclassification or sieving. Preferably, the particles will becrystalline. When an excipient such as lactose is employed, generally,the particle size of the excipient will be much greater than the inhaledmedicament within the present invention. When the excipient is lactoseit will typically be present as milled lactose, wherein not more than85% of lactose particles will have a MMD of 60–90 μm and not less than15% will have a MMD of less than 15 μm.

Intranasal sprays may be formulated with aqueous or non-aqueous vehicleswith the addition of agents such as thickening agents, buffer salts oracid or alkali to adjust the pH, isotonicity adjusting agents oranti-oxidants.

Solutions for inhalation by nebulation may be formulated with an aqueousvehicle with the addition of agents such as acid or alkali, buffersalts, isotonicity adjusting agents or antimicrobials. They may besterilised by filtration or heating in an autoclave, or presented as anon-sterile product.

Formulations for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter or polyethylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavoured basis such as sucrose and acacia ortragacanth, and pastilles comprising the active ingredient in a basissuch as gelatin and glycerin or sucrose an acacia.

Preferred unit dosage formulations are those containing an effectivedose, as hereinbefore recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavouring agents.

The compounds and pharmaceutical formulations according to the inventionmay be used in combination with or include one or more other therapeuticagents, for example selected from anti-inflammatory agents,anticholinergic agents (particularly an M₁, M₂, M₁/M₂ or M₃ receptorantagonist), other β₂-adrenoreceptor agonists, antiinfective agents(e.g. antibiotics, antivirals), or antihistamines. The invention thusprovides, in a further aspect, a combination comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof together with one or moreother therapeutically active agents, for example selected from ananti-inflammatory agent (for example a corticosteroid or an NSAID), ananticholinergic agent, another β₂-adrenoreceptor agonist, anantiinfective agent (e.g. an antibiotic or an antiviral), or anantihistamine. Preferred are combinations comprising a compound offormula (I) or a pharmaceutically acceptable salt, solvate orphysiologically functional derivative thereof together with acorticosteroid, and/or an anticholinergic, and/or a PDE-4 inhibitor.Preferred combinations are those comprising one or two other therapeuticagents.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,(e.g. as alkali metal or amine salts or as acid addition salts), orprodrugs, or as esters (e.g. lower alkyl esters), or as solvates (e.g.hydrates) to optimise the activity and/or stability and/or physicalcharacteristics (e.g. solubility) of the therapeutic ingredient. It willbe clear also that where appropriate, the therapeutic ingredients may beused in optically pure form.

Suitable anti-inflammatory agents include corticosteroids and NSAIDs.Suitable corticosteroids which may be used in combination with thecompounds of the invention are those oral and inhaled corticosteroidsand their pro-drugs which have anti-inflammatory activity. Examplesinclude methyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9αa-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g.the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g. the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,and ST-126. Preferred corticosteroids include fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, more preferably6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitorsor mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors ofleukotriene synthesis, iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine receptor agonistsor antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g.chemokine antagonists) or inhibitors of cytokine synthesis. Suitableother β₂-adrenoreceptor agonists include salmeterol (e.g. as thexinafoate), salbutamol (e.g. as the sulphate or the free base),formoterol (e.g. as the fumarate), fenoterol or terbutaline and saltsthereof.

Of particular interest is use of the compound of formula (I) incombination with a phosphodiesterase 4 (PDE4) inhibitor or a mixed PDE3/PDE4 inhibitor. The PDE4-specific inhibitor useful in this aspect of theinvention may be any compound that is known to inhibit the PDE4 enzymeor which is discovered to act as a PDE4 inhibitor, and which are onlyPDE4 inhibitors, not compounds which inhibit other members of the PDEfamily as well as PDE4. Generally it is preferred to use a PDE4inhibitor which has an IC₅₀ ratio of about 0.1 or greater as regards theIC₅₀ for the PDE4 catalytic form which binds rolipram with a highaffinity divided by the IC₅₀ for the form which binds rolipram with alow affinity. For the purposes of this disclosure, the cAMP catalyticsite which binds R and S rolipram with a low affinity is denominated the“low affinity” binding site (LPDE 4) and the other form of thiscatalytic site which binds rolipram with a high affinity is denominatedthe “high affinity” binding site (HPDE 4). This term “HPDE4” should notbe confused with the term “hPDE4” which is used to denote human PDE4.

Initial experiments may be conducted to establish and validate a[³H]-rolipram binding assay. Details of this work are given in theBinding Assays described in detail below.

Phosphodiesterase and Rolipram Binding Assays

Assay Method 1A

Isolated human monocyte PDE4 and hrPDE (human recombinant PDE4) wasdetermined to exist primarily in the low affinity form. Hence, theactivity of test compounds against the low affinity form of PDE4 can beassessed using standard assays for PDE4 catalytic activity employing 1μM [³H]cAMP as a substrate (Torphy et al., J. of Biol. Chem., Vol. 267,No. 3 pp1798–1804, 1992).

Rat brain high speed supernatants were used as a source of protein andboth enantiomers of [³H]-rolipram were prepared to a specific activityof 25.6 Ci/mmol. Standard assay conditions were modified from thepublished procedure to be identical to the PDE assay conditions, exceptfor the last of the cAMP: 50 mM Tris HCl (pH 7.5), 5 mM MgCl₂, 50 μM5′-AMP and 1 nM of [³H]-rolipram (Torphy et al., J. of Biol. Chem., Vol.267, No. 3 pp1798–1804, 1992). The assay was run for 1 hour at 30° C.The reaction was terminated and bound ligand was separated from freeligand using a Brandel cell harvester. Competition for the high affinitybinding site was assessed under conditions that were identical to thoseused for measuring low affinity PDE activity, expect that [³H]-cAMP wasnot present.

Assay Method 1B

Measurement of Phosphodiesterase Activity

PDE activity was assayed using a [³H]cAMP SPA or [³H]cGMP SPA enzymeassay as described by the supplier (Amersham Life Sciences). Thereactions were conducted in 96-well plates at room temperature, in 0.1ml of reaction buffer containing (final concentrations): 50 mM Tris-HCl,pH 7.5, 8.3 mM MgCl₂, 1.7 mM EGTA, [³H]cAMP or [³H] cGMP (approximately2000 dpm/pmol), enzyme and various concentrations of the inhibitors. Theassay was allowed to proceed for 1 hr and was terminated by adding 50 μlof SPA yttrium silicate beads in the presence of zinc sulfate. Theplates were shaken and allowed to stand at room temperature for 20 min.Radiolabeled product formation was assessed by scintillationspectrometry.

[³H]R-Rolipram Binding Assay

The [³H]R-rolipram binding assay was performed by modification of themethod of Schneider and co-workers, see Nicholson, et al., TrendsPharmacol. Sci., Vol. 12, pp.19–27 (1991) and McHale et al., Mol.Pharmacol., Vol.39, 109–113 (1991). R-Rolipram binds to the catalyticsite of PDE4 see Torphy et al., Mol. Pharmacol., Vol. 39, pp. 376–384(1991). Consequently, competition for [³H]R-rolipram binding provides anindependent confirmation of the PDE4 inhibitor potencies of unlabeledcompetitors. The assay was performed at 30° C. for 1 hr in 0.5 μl buffercontaining (final concentrations): 50 mM Tris-HCl, pH 7.5, 5 mM MgCl₂,0.05% bovine serum albumin, 2 nM [³H]R-rolipram (5.7×104 dpm/pmol) andvarious concentrations of non-radiolabeled inhibitors. The reaction wasstopped by the addition of 2.5 ml of ice-cold reaction buffer (without[³H]-R-rolipram) and rapid vacuum filtration (Brandel Cell Harvester)through Whatman GF/B filters that had been soaked in 0.3%polyethylenimine. The filters were washed with an additional 7.5 ml ofcold buffer, dried, and counted via liquid scintillation spectrometry.

The preferred PDE4 inhibitors of use in this invention will be thosecompounds which have a salutary therapeutic ratio, i.e., compounds whichpreferentially inhibit cAMP catalytic activity where the enzyme is inthe form that binds rolipram with a low affinity, thereby reducing theside effects which apparently are linked to inhibiting the form whichbinds rolipram with a high affinity. Another way to state this is thatthe preferred compounds will have an IC₅₀ ratio of about 0.1 or greateras regards the IC₅₀ for the PDE4 catalytic form which binds rolipramwith a high affinity divided by the IC₅₀ for the form which bindsrolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4inhibitor has an IC₅₀ ratio of about 0.1 or greater; said ratio is theratio of the IC₅₀ value for competing with the binding of 1 nM of[³H]R-rolipram to a form of PDE4 which binds rolipram with a highaffinity over the IC₅₀ value for inhibiting the PDE4 catalytic activityof a form which binds rolipram with a low affinity using 1 μM[³H]-cAMPas the substrate.

Examples of useful PDE4 inhibitors are:

-   (R)-(+)-1-(4-bromobenzyl)4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;-   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone;-   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone;-   cis    4-cyano-4-(3-cyclopentyloxy-4methoxyphenyl)cyclohexan-1-carboxylic    acid];-   cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];-   (R)-(+)-ethyl    [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate;    and-   (S)-(−)-ethyl    [4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-ylidene]acetate.

Most preferred are those PDE4 inhibitors which have an IC₅₀ ratio ofgreater than 0.5, and particularly those compounds having a ratio ofgreater than 1.0. Preferred compounds are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];these are examples of compounds which bind preferentially to the lowaffinity binding site and which have an IC₅₀ ratio of 0.1 or greater.

Other compounds of interest include:

-   Compounds set out in U.S. Pat. No. 5,552,438 issued 3 Sep. 1996;    this patent and the compounds it discloses are incorporated herein    in full by reference. The compound of particular interest, which is    disclosed in U.S. Pat. No. 5,552,438, is    cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylic    acid (also known as cilomalast) and its salts, esters, pro-drugs or    physical forms;

AWD-12–281 from Asta Medica (Hofgen, N. et al. 15th EFMC Int Symp MedChem (September 6–10, Edinburgh) 1998, Abst P.98; CAS reference No.247584020-9); a 9-benzyladenine derivative nominated NCS-613 (INSERM);D-4418 from Chiroscience and Schering-Plough; a benzodiazepine PDE4inhibitor identified as CI-1018 (PD-168787) and attributed to Pfizer; abenzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34from Kyowa Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J[Annu Cong Eur Resp Soc (September 19–23, Geneva) 1998] 1998, 12 (Suppl.28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and apthalazinone (WO99/147505, the disclosure of which is herebyincorporated by reference) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/ PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/ UM565 from Vemalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther,1998, 284(1): 162), andT2585.

Other possible PDE-4 and mixed PDE3/ PDE4 inhibitors include thoselisted in WO01/13953, the disclosure of which is hereby incorporated byreference.

Suitable anticholinergic agents are those compounds that act asantagonists at the muscarinic receptor, in particular those compoundswhich are antagonists of the M₁ and M₂ receptors. Exemplary compoundsinclude the alkaloids of the belladonna plants as illustrated by thelikes of atropine, scopolamine, homatropine, hyoscyamine; thesecompounds are normally administered as a salt, being tertiary amines.These drugs, particularly the salt forms, are readily available from anumber of commercial sources or can be made or prepared from literaturedata via, to wit:

-   Atropine—CAS-51-55-8 or CAS-51-48-1 (anhydrous form), atropine    sulfate—CAS-5908-99-6; atropine oxide—CAS-4438-22-6 or its HCl    salt—CAS-4574-60-1 and methylatropine nitrate—CAS-52-88-0.-   Homatropine—CAS-87-00-3, hydrobromide salt—CAS-51-56-9,    methylbromide salt—CAS-80-49-9.-   Hyoscyamine (d, l)—CAS-101-31-5, hydrobromide salt—CAS-306-03-6 and    sulfate salt—CAS-6835-16-1.-   Scopolamine—CAS-51-34-3, hydrobromide salt—CAS-6533-68-2,    methylbromide salt—CAS-155-41-9.

Preferred anticholinergics include ipratropium (e.g. as the bromide),sold under the name Atrovent, oxitropium (e.g. as the bromide) andtiotropium (e.g. as the bromide) (CAS-139404-48-1). Also of interestare: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9),anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidiniumbromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamideiodide (CAS-71-81-8), mepenzolate bromide (U.S. Pat. No. 2,918,408),tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocycliummethylsulfate (Tral, CAS-115-63-9). See also cyclopentolatehydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-75-4),trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine(CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, ormethoctramine, and the compounds disclosed in WO01/04118, the disclosureof which is hereby incorporated by reference.

Suitable antihistamines (also referred to as H₁-receptor antagonists)include any one or more of the numerous antagonists known which inhibitH₁-receptors, and are safe for human use. All are reversible,competitive inhibitors of the interaction of histamine withH₁-receptors. The majority of these inhibitors, mostly first generationantagonists, have a core structure, which can be represented by thefollowing formula:

This generalized structure represents three types of antihistaminesgenerally available: ethanolamines, ethylenediamines, and alkylamines.In addition, other first generation antihistamines include those whichcan be characterized as based on piperizine and phenothiazines. Secondgeneration antagonists, which are non-sedating, have a similarstructure-activity relationship in that they retain the core ethylenegroup (the alkylamines) or mimic the tertiary amine group withpiperizine or piperidine. Exemplary antagonists are as follows:

Ethanolamines: carbinoxamine maleate, clemastine fumarate,diphenylhydramine hydrochloride, and dimenhydrinate.

Ethylenediamines: pyrilamine amleate, tripelennamine HCl, andtripelennamine citrate.

Alkylamines: chlropheniramine and its salts such as the maleate salt,and acrivastine.

Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl,cyclizine lactate, meclizine HCl, and cetirizine HCl.

Piperidines: Astemizole, levocabastine HCl, loratadine or itsdescarboethoxy analogue, and terfenadine and fexofenadine hydrochlorideor another pharmaceutically acceptable salt.

Azelastine hydrochloride is yet another H₁ receptor antagonist which maybe used in combination with a PDE4 inhibitor.

Examples of preferred anti-histamines include methapyrilene andloratadine.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with aPDE4 inhibitor.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with acorticosteroid.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan anticholinergic.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan antihistamine.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together with aPDE4 inhibitor and a corticosteroid.

The invention thus provides, in a further aspect, a combinationcomprising a compound of formula (I) a pharmaceutically acceptable salt,solvate or physiologically functional derivative thereof together withan anticholinergic and a PDE-4 inhibitor.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical formulation and thus pharmaceuticalformulations comprising a combination as defined above together with aphysiologically acceptable diluent or carrier represent a further aspectof the invention.

The individual compounds of such combinations may bib administeredeither sequentially or simultaneously in separate or combinedpharmaceutical formulations. Appropriate doses of known therapeuticagents will be readily appreciated by those skilled in the art.

According to a further aspect of the invention, there is provided aprocess for preparing a compound of formula (I), (Ia), (Ib) or (Ic) or asalt, solvate, or physiologically functional derivative thereof whichcomprises a process (a),b),(c), (d) or (e) as defined below followed bythe following steps in any order:

-   -   (i) optional removal of any protecting groups;    -   (ii) optional separation of an enantiomer from a mixture of        enantiomers;    -   (iii) optional conversion of the product to a corresponding        salt, solvate, or physiologically functional derivative thereof.

In one general process (a), a compound of formula (I), (Ia), (Ib) or(Ic) may be obtained by deprotection of a protected intermediate, forexample of formula (II):

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, m, and n areas defined for the compound of formula (I), (Ia), (Ib) or (Ic), and R¹²,R¹³, and R¹⁴ are each independently either hydrogen or a protectinggroup provided that at least one of R¹², R¹³, and R¹⁴ is a protectinggroup, and R¹⁸ is either hydrogen or a protecting group.

Suitable protecting groups may be any conventional protecting group suchas those described in “Protective Groups in Organic Synthesis” byTheodora W Greene and Peter G M Wuts, 3rd edition (John Wiley & Sons,1999). Examples of suitable hydroxyl protecting groups represented byR¹² and R¹³ are esters such as acetate ester, aralkyl groups such asbenzyl, diphenylmethyl, or triphenylmethyl, and tetrahydropyranyl.

Examples of suitable amino protecting groups represented by R¹⁴ includebenzyl, α-methylbenzyl, diphenylmethyl, triphenylmethyl,benzyloxycarbonyl, tert-butoxycarbonyl, and acyl groups such astrichloroacetyl or trifluoroacetyl.

As will be appreciated by the person skilled in the art, use of suchprotecting groups may include orthogonal protection of groups in thecompounds of formula (II) to facilitate the selective removal of onegroup in the presence of another, thus enabling selectivefunctionalisation of a single amino or hydroxyl function. For example,the —CH(OH) group may be orthogonally protected as —CH(OR¹⁸) using, forexample, a trialkylsilyl group such as triethylsilyl. A person skilledin the art will also appreciate other orthogonal protection strategies,available by conventional means as described in Theodora W Greene andPeter G M Wuts (see above).

The deprotection to yield a compound of formula (I), (Ia), (Ib) or (Ic)may be effected using conventional techniques. Thus, for example, whenR¹², R¹³, and/or R¹⁴ is an aralkyl group, this may be cleaved byhydrogenolysis in the presence of a metal catalyst (e.g. palladium oncharcoal).

When R¹² and/or R¹³ is tetrahydropyranyl this may be cleaved byhydrolysis under acidic conditions. Acyl groups represented by R¹⁴ maybe removed by hydrolysis, for example with a base such as sodiumhydroxide, or a group such as trichloroethoxycarbonyl may be removed byreduction with, for example, zinc and acetic acid. Other deprotectionmethods may be found in Theodora W Greene and Peter G M Wuts (seeabove). In a particular embodiment of process (a), R¹² and R¹³ maytogether represent a protecting group as in the compound of formula(III):

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R¹⁴, R¹⁸ m,and n are as defined for the compound of formula (I), (Ia), (Ib) or(Ic), R¹⁵ and R¹⁶ are independently selected from hydrogen, C₁₋₆alkyl,or aryl. In a preferred aspect, both R¹⁵ and R¹⁸ are methyl.

The compound of formula (III) may be converted to a compound of formula(I), (Ia), (Ib) or (Ic) by hydrolysis with dilute aqueous acid, forexample acetic acid or hydrochloric acid in a suitable solvent or bytransketalisation in an alcohol, for example ethanol, in the presence ofa catalyst such as an acid (for example, toluenesulphonic acid) or asalt (such as pyridinium tosylate) at normal or elevated temperature.

It will be appreciated that the protecting groups R¹², R¹³, R¹⁴ and R¹⁸(including the cyclised protecting group formed by R¹⁵ and R¹⁶ asdepicted in formula (Ill) may be removed in a single step orsequentially. The precise order in which protecting groups are removedwill in part depend upon the nature of said groups and will be readilyapparent to the skilled worker. Preferably, when R¹⁵ and R¹⁶ togetherform a protecting group as in formula (III) this protecting group isremoved together with any protecting group on the CH(OH) moiety,followed by removal of R¹⁴.

Depending on the nature of the group R⁶, some compounds of formulae (II)and (III) wherein R¹⁴ is hydrogen may be prepared from the correspondingcompound of formula (IV):

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, R¹², R¹³, m,and n are as defined for the compound of formula (II) or (III).

In this process, the group R⁶ should be chosen such that it issufficiently stable to resist hydrolysis under the conditions requiredto open the oxazolidine ring in the compound of formula (IV) to give acompound of formula (II) or (III).

The conversion of a compound of formula (IV) to a compound of formula(II) or (III) may be effected by treatment with a base, for example anon-aqueous base, such as potassium trimethylsilanolate, or an aqueousbase such as aqueous sodium hydroxide, in a suitable solvent such astetrahydrofuran.

Compounds of formula (IV) may be prepared from the correspondingcompound of formula (V):

or a salt or solvate thereof, wherein R⁴, R⁵, R¹², R¹³, m and n are asdefined for the compound of formula (II);by coupling with a compound of formula (VI) or a precursor thereof:

wherein R¹, R², and R³ are as defined for the compound of formula (I) oreach may independently represent a precursor for said groups, and L is aleaving group, such as a halo group (typically, bromo or iodo) or ahaloalkyl sulphonate (typically, trifluoromethanesulphonate), followedby reduction.

The coupling of a compound of formula (V) with a compound of formula(VI) or a precursor thereof is conveniently effected in the presence ofa catalyst system such as bis(triphenylphosphine) palladium dichloridewith an organic base such as a trialkylamine, for example triethylamine,in a suitable solvent for example acetonitrile or dimethylformamide. Theresulting alkyne may then be reduced, either with or without beingisolated to form the compound of formula (IV). The reduction may beeffected by any suitable method such as hydrogenation in the presence ofa catalyst, for example palladium/charcoal or platinum oxide.

Compounds of formula (VI) are commercially available or may be preparedby methods well known to the person skilled in the art.

A suitable precursor of the compound of formula (VI) would be a compoundof formula (VI) in which one or more of the substituents R¹, R², and R³is a group which is convertible to the desired group R¹, R², and/or R³.For example, when R¹ is to be —XR⁶ and R⁶ is to be the group (a), asuitable precursor of the compound of formula (VI) may have the primaryamine in place of the substituent R⁶, such that the desired substituentR¹ may be formed by reaction with an appropriate isocyanate to give anurea group —XNHC(O)NHCH₂C(O)O(C₁₋₆alkyl). Conversion to the desiredgroup R¹ may then be effected by standing the urea in an inert solvent,optionally in the presence of a base such as an inorganic base, forexample potassium carbonate or sodium hydride, or an organic base, forexample triethylamine or diisopropylethylamine, either before or afterthe coupling with the compound of formula (V). Alternatively the ureaester group depicted above may be hydrolysed to the corresponding ureacarboxylic acid, followed by treatment with a mineral acid such ashydrochloric acid, or a strong organic acid such as asp-toluenesulphonic acid, to give the desired hydantoin group. Theprimary as amine may be formed by reduction of a corresponding nitrogroup.

As a further example, when the group R¹ is to be —XR⁶ and R⁶ is to bethe group (b), a suitable precursor might have a primary urea in placeof the group R⁶, such that the desired substituent R¹ may be formed byreaction with an appropriate compound of formula (C₁₋₆alkyl)O₂CCR⁸R⁹L,wherein L is a leaving group as in the compound of formula (VI),typically chloro.

As a yet further example, when the group R¹ is to be —XR⁶ and R⁶ is tobe the group (c), a suitable precursor might have a formyl group or agroup —C(O)R⁸ in place of the group R⁶, such that the desiredsubstituent R¹ may be formed by reaction with NaCN and (NH₄)₂CO₃ as inG. Wagner, B. Voigt and I. Lischke, Pharmazie, 1981, 36, 467.

As a still further example, when the group R¹ is to be —XR⁶ and R⁶ is tobe the group (d), a suitable precursor might have a primary amine inplace of the group R⁶, such that the desired substituent R¹ may beformed by reaction with an appropriate isocyanate to give a urea group—NHC(O)NHCH₂CH₂L, wherein L is a leaving group as in the compound offormula (VI), typically chloro. Conversion to the desired group R¹ maythen be effected by standing the urea in an inert solvent, for exampleN,N-dimethylformamide, in the presence of a base such as an inorganicbase, for example potassium carbonate or sodium hydride, or an organicbase, for example triethylamine or diisopropylethylamine, either beforeor after the coupling with the compound of formula (V).

As another example, if the group R¹ is to be —XR⁶ and R⁶ is to be thegroup (f), a suitable precursor might have an isocyanate in place of thegroup R⁶. Conversion to the desired group R⁶ could then be effected byreaction with a masked amino-aldehyde of formula H₂NCH₂CH(OC₁₋₆alkyl|)₂in an inert solvent such as dichloromethane. Cyclization to the desiredR⁶ group could then be effected by unmasking the aldehyde, for exampleby treatment with an acid such as aqueous trifluoroacetic acid, as in E.R. Parmee et al., Bioorg. Med. Chem. Lett. 1999, 9, 749–754.

As a further example, if the group R¹ is to be XR⁶ and R⁶ is to be thegroup (g) a suitable precursor might have a group —COCH₂NH₂ in place ofR⁶. Conversion to the desired group R⁶ may be effected by treating withcyanic acid, according to the procedure described by Rupe, Chem. Ber1894, 27, 582.

As another example, if the group R¹ is to be —CH₂R⁶ and R⁶ is to be thegroup (h), a suitable precursor might have a group Br in place of thegroup R⁶, such that the desired substituent R¹ may be formed by couplingwith the anion derived by deprotonation of parabanic acid or a suitablederivative thereof, for example by treatment with sodium hydride.Alternatively, if the group R¹ is to be —R⁶ and R⁶ is to be the group(h), a suitable precursor might have an iodo group in place of the groupR⁶, such that the desired substituent R¹ may be formed by a palladiumcatalysed condensation with parabanic acid or a suitable derivativethereof.

An alternative precursor when R¹ is to be —XR⁶ and R⁶ is to be the group(h) would have a primary urea in place of the group R⁶. Conversion tothe desired group R⁶ could then be effected by reaction with(C₁₋₆alkyl)O₂CCOCl.

As another example, if the group R¹ is to be XR⁶ and R⁶ is to be thegroup (i), a suitable precursor might have a group —NHOH in place of thegroup R⁶. Conversion to the desired group R⁶ could then be effected byreaction with chlorocarbonylisocyanate as in M. S. Malamas et el, Eur.J. Med. Chem. 2001, 36, 31–42.

As another example, if the group R¹ is to be XR⁶ and R⁶ is to be thegroup (j), a suitable precursor might have a group —NHNH₂ in place ofthe group R⁶. Conversion to the desired group R⁶ could then be effectedby reaction with urea in a solvent such as N,N-dimethylformamide, as inJ. A. Lenoir and B. L. Johnson, Tetrahedron Letters, 1973, 5123–5126.

As a still further example, when R¹ is to be the group XR⁶ and Re is tobe the group (k) a suitable precursor might have an isocyanate in placeor the group R⁶ such that the desired substituent R¹ may be formed bytreating the isocyanate with hydroxylamine and a chloroformate, eg. analkyl chloroformate such as ethyl chloroformate, and treating theresulting compound with base, eg. NaOH, to form the desired heterocyclicring. (G. Zinner and R. Weber, Arch. Pharm. Ber. 1965, 298, 580–587).

As another example, when the group R¹ is to be XR⁶ and R⁶ is to be thegroup (I) a suitable presursor might be an isocyanate in place of thegroup R⁶. This may be treated with an alkyl carbazate eg. ethylcarbazate and the resulting product treated with a base eg. potassiumhydroxide to form the desired heterocycle (W Adam and N Carballeira J.Am. Chem. Soc., 1984, 106, 2874).

Compounds of formula (V) may be prepared by coupling a compound offormula (VII):

or a salt or solvate thereof, wherein R¹² and R¹³ are as defined for thecompound of formula (V) with a compound of formula (VIII):L¹CR⁴R⁵(CH₂)_(m)—O—(CH₂)_(n-2)—C≡CH  (VIII)

Wherein R⁴, R⁵, m and n are as defined for the compound of formula (V)and L¹ is a leaving group, for example a halo group, (typically bromo oriodo) or a sulphonate such as an alkyl sulphonate (typically methanesulphonate) an aryl sulphonate (typically toluenesulphonate) or ahaloalyalkylksulphonate (typically trifluoromethane sulphonate).

The coupling of a compound of formula (VII) with a compound of formula(VIII) may be effected in the presence of a base, such as a metalhydride, for example sodium hydride, or an inorganic base such as cesiumcarbonate, in an aprotic solvent, for example N,N-dimethylformamide.

Compounds of formula (VIII) may be prepared from the correspondingdihaloalkane and hydroxyalkyne by conventional chemistry, typically inthe presence of an inorganic base, such as aqueous sodium hydroxide,under phase transfer conditions in the presence of a salt such astetraalkylammonium bromide.

Compounds of formula (VII) may be prepared by ring closure of a compoundof formula (IX):

wherein R¹² and R¹³ are as defined for the compound of formula (VII) andR¹⁷ is C₁₋₆alkyl, for example tert-butyl, or aryl, for example phenyl.The ring closure may be effected by treatment with a base, such as ametal hydride, for example sodium hydride, in the presence of an aproticsolvent, for example, N,N-dimethylformamide.

Compounds of formula (IX) may be prepared from the corresponding ketoneof formula (X):

wherein R¹² and R¹³ and R¹⁷ are as defined for the compound of formula(IX), by reduction by any suitable method, for example by treatment withborane, in the presence of a chiral catalyst, such asCBS-oxazaborolidine, in a suitable solvent such as tetrahydrofuran.

The compound of formula (X) may be prepared from the correspondinghalide of formula (XI):

wherein R¹² and R¹³ are as defined for the compound of formula (IV) andY is a halo, suitably bromo.

The conversion of a compound of formula (XI) to a compound of formula(X) may be effected by reaction with the protected amine HN(COOR¹⁷)₂wherein R¹⁷ is as defined for the compound of formula (X) in thepresence of an inorganic base such as cesium carbonate, followed byselective removal of one of the COOR¹⁷ groups, for example by treatmentwith an acid such as trifluoroacetic acid.

Compounds of formula (XI) may be prepared from the correspondingcompound having free hydroxymethyl and hydroxy substituents (whichitself may be prepared from2-bromo-1-(4-hydroxy)-3-hydroxymethyl-phenethyl)ethanone, thepreparation of which is described in GB2140800, by treatment with2-methoxypropane in acetone in the presence of an acid e.g.p-toluenesulphonic acid in a nitrogen atmosphere or by other standardmethods) by forming the protected groups R¹³OCH₂— and R¹²O— wherein R¹³and R¹² are as defined for the compound of formula (XI). Such methodsare described in DE 3513885 (Glaxo).

Compounds of formulae (II) or (III) where R¹⁴ is hydrogen or aprotecting group may be prepared according to the general methodsdescribed below.

In a further process (b) a compound of formula (I), (Ia), (Ib) or (Ic)may be obtained by alkylation of an amine of formula (XII):

wherein R¹², R¹³, R¹⁴ and R¹⁸ are each independently either hydrogen ora protecting group. Suitable protecting groups are discussed in thedefinition of compounds of formula (II) and (III); with a compound offormula (XIII):

wherein R¹, R², R³, R⁴, R⁵, m, and n are as defined for the compound offormula (I), (Ia) or (Ib) and L¹ is a leaving group as herein beforedefined for the compound of formula (VIII); followed by removal of anyprotecting groups present by conventional methods as described above forthe deprotection of compounds of formula (II) and (III). For speed ofreaction, L¹ is preferably bromo or is converted to bromo in situ, fromthe corresponding compound wherein L¹ is methanesulphonate, for exampleby addition of tetrabutylammonium bromide to the reaction mixture.

The compound of formula (I), (Ia) or (Ib) may be formed directly (whenin the compound of formula (XII) R¹², R¹³, R¹⁴ and R¹⁸ are eachhydrogen) or via a compound of formula (II) or (III) which may or maynot be isolated (when in the compound of formula (XII) at least one ofR¹², R¹³ R¹⁴ and R¹⁸ is a protecting group).

The reaction of compounds of formulae (XII) and (XIII) is optionallyeffected in the presence of an organic base such as a trialkylamine, forexample, diisopropylethylamine, and in a suitable solvent for exampleN,N-dimethylformamide, or acetonitrile.

Compounds of formula (XII) are known in the art (for example EP-A0947498) or may be readily prepared by a person skilled in the art, forexample from the corresponding halide of formula (XI) as defined above.The conversion of a compound of formula (XI) to a compound of formula(XII) may be effected by reaction with sodium azide in a suitablesolvent, for example N,N-dimethylformamide, to give the correspondingcompound wherein Y denotes N₃. The carbonyl group may then be reduced tothe corresponding alcohol by any suitable method, for example bytreatment with borane, in the presence of a chiral catalyst, such as(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole,in a suitable solvent such as tetrahydrofuran. The azide group may bereduced to the corresponding amine group by any suitable method, forexample by catalytic hydrogenation in the presence of a catalyst such aspalladium/charcoal or platinum oxide.

Compounds of formula (XIII) may be prepared by coupling a compound offormula (VI) or a precursor thereof (wherein one or more of thesubstituents R¹, R², or R³ is a group which is convertible to R¹, R², orR³) with a compound of formula (VII) as shown above, followed byreduction.

The coupling of a compound of formula (VIII) with a compound (VI) may beeffected by in the presence of a catalyst system such as bis(triphenylphosphine) palladium dichloride with an organic base such as atrialkylamine, for example, triethylamine, in a suitable solvent, forexample acetonitrile or N,N-dimethylformamide. The resulting alkyne maythen be reduced, either with or without being isolated, to form thecompound of formula (XIII). The reduction may be effected by anysuitable method such as hydrogenation in the presence of a catalyst, forexample, palladium/charcoal or platinum oxide. If necessary, thesubstituents R¹, R², and/or R³ may be formed by conventional conversionswhere a precursor is present.

In a yet further process (c) a compound of formula (I), (Ia), (Ib) or(Ic) may be obtained by reduction of a compound of formula (XIV):

wherein R¹, R², R³, R⁴, R⁵, m and n are as defined for formula (I) andR¹², R¹³, R¹⁴ and R¹⁸ each independently represent a hydrogen atom or aprotecting group as defined above.

The reduction may be effected by any suitable method such ashydrogenation in the presence of a catalyst, for example,palladium/charcoal or platinum oxide.

It will be appreciated that where R¹², R¹³, R¹⁴ and R¹⁸ each representhydrogen, the reduction will yield a compound of formula (I), but whereone or more or R¹², R¹³, R¹⁴ and R¹⁸ represent a protecting group thenreduction will yield a compound of formula (II) or (III), which may thenbe deprotected to give a compound of formula (I).

A compound of formula (XIV) may be prepared by reacting a compound offormula (XII) as herein before defined with a compound of formula (XV):

wherein R¹, R², R³, R⁴, R⁵, m, and n are as defined for the compound offormula (I), (Ia) or (Ib) and L¹ is as defined for the compound offormula (XIII).

The reaction of compounds of formulae (XIV) and (XV) is optionallyeffected in the presence of an organic base such as a trialkylamine, forexample, diisopropylethylamine, and in a suitable solvent for exampleN,N-dimethylformamide.

The compound of formula (XV) may be prepared by coupling a compound offormula (VI) as defined above with a compound of formula (VIII) asdefined above, as described for the first stage of the preparation ofcompounds (XIII), without the reduction step.

An alkyne of formula (XV) may also be prepared by reacting a compound offormula (XVI):L²CR⁴R⁵(CH₂)mL³  (XVI)

Wherein R⁴, R⁵ and n are as defined hereinabove and L² and L³ eachrepresent a leaving group, which groups may independently be selectedfor example from those defined above for L and L¹, with a compound offormula (XVII):

using conventional methods, for example as described for the preparationof compounds (VIII).

Compounds of formula (XVII) may be prepared by reacting a hydroxyalkyneHO(CH₂)n-2≡with a compound of formula (VI) using methods analogous to thosedescribed above for coupling a compound (V) with a compound (VI).

In a further process (d) a compound of formula (I), (Ia), (Ib) or (Ic)may be prepared by reacting a compound of formula (XVIII):

wherein R¹², R¹³ and R¹⁸ are as hereinbefore defined and L⁴ is a leavinggroup, is reacted with an amine of formula (XIX):

followed by removal of any protecting groups present by conventionalmethods as described above for the deprotection of compounds of formula(II).

The reaction may be effected using conventional conditions for suchdisplacement reactions.

Compounds of formula (XVIII) may be prepared by methods known in theart.

Compounds of formula (XIX) may be prepared by reacting a compound offormula (XIII) with an amine R¹⁴NH₂.

In a further process (e) a compound of formula (I), (Ia) or (Ib) may beprepared by removal of a chiral auxiliary from a compound of formula(IIa):

wherein R¹, R², R³, R⁴, R⁵, m and n are as defined for formula (I), R¹²,R¹³, R¹⁴ and R¹⁸ each independently represent a hydrogen atom or aprotecting group as defined above and R¹⁹ represents a chiral auxiliary.

A “chiral auxiliary” is a moiety that is introduced into a molecule toinfluence the stereochemistry of the product formed, and is removed inwhole or part at a later time. A chiral auxiliary may simultaneouslyfunction as a protecting group.

Many chiral auxiliaries are commercially available, and persons skilledin the art would choose one based on the properties desired i.e. theabsolute stereochemistry desired and compatibility with the processesbeing used. Chiral auxiliaries suitable for use in this process includebut are not limited to the S-isomer and/or the R-isomer of phenylglycinol and substituted derivatives thereof.

The chiral auxiliary is preferably a moiety of the formula:

or a single enantiomer thereof, wherein R²⁰ represents C₁₋₆alkyl oroptionally substituted phenyl or benzyl wherein the optionalsubstitution is one or more independently selected from C₁₋₆alkyl,halogen, hydroxy, C₁₋₆alkoxy or nitro e.g. para-hydroxyphenyl.

More preferably the chiral auxiliary is a moiety:

wherein R²⁰ is as defined above. Alternatively it may be a moiety offormula:

wherein R²⁰ is as defined above.

Preferably R²⁰ represents phenyl optionally substituted as describedabove. Most preferably R²⁰ represents unsubstituted phenyl.

The chiral auxiliary in this process may typically be removed byhydrogenolysis using for example a palladium on carbon catalyst orpreferably using palladium hydroxide (Pearlman's catalyst).Advantageously when Pearlman's catalyst is used the removal of thechiral auxiliary is most efficient. This method of removal is especiallysuitable where R²⁰ is phenyl or a substituted phenyl. Alternatively thenitrogen, to which the auxiliary is attached, may be derivatised underoxidising conditions to form the N-oxide before elimination by heatingto give a secondary amine.

A compound of formula (IIa) may be prepared by reduction of thecorresponding alkyne of formula (XIVa):

wherein R¹, R², R³, R⁴, R⁵, m and n are as defined for formula (I) andR¹², R¹³, R¹⁴ and R¹⁸ each independently represent a hydrogen atom or aprotecting group as defined above. Preferably in the compounds offormulae (IIa) and (XIVa) the protecting groups R¹² and R¹³ togetherform a group —CR¹⁵R¹⁶— as in the compounds of formula (III).

Reduction of an alkyne of formula (XIVa) may be effected by methods wellknown in the art, for example by catalytic hydrogenation, usingpalladium on charcoal or more preferably palladium hydroxide (Pearlman'scatalyst). The chiral auxiliary may also be removed under reductiveconditions. Advantageously, therefore the reduction of the alkyne andremoval of the chiral auxiliary may be effected concomitantly in a‘one-pot’ reaction.

An alkyne of formula (XIVa) may be prepared by reaction of a compound offormula (XX)

with a compound of formula (VI) under conditions described above forcoupling of compounds (V) and (VI).

A compound of formula (XX) may be prepared by reacting a compound offormula (XIIa):

with an aldehyde of formula (XXI):

using known methods for effecting reductive amination, e.g. sodiumtriacetoxyborohydride in a solvent such as chloroform

An aldehyde of formula (XXI) may be prepared from a corresponding halideof formula (VIII) using standard techniques such as treatment withsodium bicarbonate in a solvent such as DMSO at elevated temperature,preferably in the range 130–160° C.

A compound of formula (XIIa) may be prepared from a compound of formula(Xa):

Wherein R¹², R¹³ and R¹⁹ are as hereinbefore defined by treatment with areducing agent such as a hydride source e.g. sodium borohydride.Preferably this process takes place in the presence of an inert metalsalt such as calcium chloride suitably at non-extreme temperatures e.g.below ambient, such as 0° C. This allows the desired stereochemistry tobe introduced efficiently with good enantiomeric excess at an earlystage in the synthesis, using inexpensive and relatively harmlessreagents. Furthermore, the enantiomeric excess may be increased byrecrystallisation of the product of this process.

A compound of formula (Xa) may be prepared from a compound of formula(XI) as hereinbefore defined by reaction with an appropriate chiralamine, e.g. (S)-phenylglycinol, in the presence of a non-nucleophilicbase in an inert solvent at non-extreme temperatures.

A detailed description of a process analogous to Route (e) may be foundin published International Application Number WO/0196278.

In the above process (e) it is preferred that the protecting groups R¹²and R¹³ together form a protecting group as depicted in formula (III).

It will be appreciated that in any of the routes (a) to (e) describedabove, the precise order of the synthetic steps by which the variousgroups and moieties are introduced into the molecule may be varied. Itwill be within the skill of the practitioner in the art to ensure thatgroups or moieties introduced at one stage of the process will not beaffected by subsequent transformations and reactions, and to select theorder of synthetic steps accordingly.

The enantiomeric compounds of the invention may be obtained (i) byseparation of the components of the corresponding racemic mixture, forexample, by means of a chiral chromatography column, enzymic resolutionmethods, or preparing and separating suitable diastereoisomers, or (ii)by direct synthesis from the appropriate chiral intermediates by themethods described above.

Optional conversions of a compound of formula (I), (Ia) or (Ib) to acorresponding salt may conveniently be effected by reaction with theappropriate acid or base. Optional conversion of a compound of formula(I), (Ia) or (Ib) to a corresponding solvate or physiologicallyfunctional derivative may be effected by methods known to those skilledin the art.

According to a further aspect, the present invention provides novelintermediates for the preparation of compounds of formula (I), (Ia) or(Ib), for example:

-   compounds of formula (II), (Ill) and XIV) as defined above, or an    optical isomer, a salt, or a protected derivative thereof;    particularly, a compound selected from:-   3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione;-   3-(3-{3-[(7-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}phenyl)imidazolidine-2,4-dione;-   1-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl{phenyl)imidazolidine-2-one;    and-   1-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione;-   3-(3-{4-[(6-{[(2S)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione;-   3-(4-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione;-   3-(2-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione;-   3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzyl)imidazolidine-2,4-dione;-   3-(3-{5-[(5-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}pentyl)oxy]pentyl}phenyl)imidazolidine-2,4-dione;-   3-(3-{5-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]pentyl}phenyl)imidazolidine-2,4-dione;-   3-(3-{6-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]hexyl}phenyl)imidazolidine-2,4-dione;-   3-(3-{6-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]hexyl}phenyl)imidazolidine-2,4-dione;-   (5S)-5-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzyl)-5-methylimidazolidine2,4-dione;-   2-[3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-2,4-dioxoimidazolidin-1-yl]acetamide;-   5-{4-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzyl}imidazolidine-2,4-dione;-   3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-5,5-dimethylimidazolidine-2,4-dione;-   3-(3-{3-[(7-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}phenyl)-1-(methylsulfonyl)imidazolidine-2,4-dione;-   1-(3-{3-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]propyl}phenyl)imidazolidine-2,4-dione;-   N-[1-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzyl)-2,5-dioxoimidazolidin-4-yl]urea;-   3-Benzyl-1-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl]imidazolidine-2,4-dione;-   1-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl{phenyl)-3-methylimidazolidine-2,4-dione;-   Ethyl    [3-(3-{4-[(6-{[(2-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-2,5-dioxoimidazolidin-1-yl]acetate;-   2-[3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-2,5-dioxoimidazolidin-1-yl]acetamide;-   1-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzyl)imidazolidine-2,4-dione;-   3-Benzyl-1-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione;-   3-(3-{4-[(6-{[(2R)-2-(2,2-imethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino{hexyl)oxy]butyl}phenyl)-1-(methylsulfonyl)imidazolidine-2,4-dione;    and-   4(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-1,2,4-triazolidine-3,5-dione.

For a better understanding of the invention, the following Examples aregiven by way of illustration.

SYNTHETIC EXAMPLES

Throughout the examples, the following abbreviations are used:

-   LCMS: Liquid Chromatography Mass Spectrometry-   MS: mass spectrum-   TSP+ve: thermospray mass spectrum positive mode-   HPLC: high pressure liquid chromatography-   RT: retention time-   THF: tetrahydofuran-   DMF: N,N-dimethylformamide-   EtOAc: ethyl acetate-   Et₂O: diethyl ether-   EtOH: ethanol-   MeOH: methanol-   bp: boiling point-   ca: circa-   h: hour(s)-   min: minute(s)

All temperatures are given in degrees centigrade.

Silica gel refers to Merck silica gel 60 Art number 7734.

Flash silica gel refers to Merck silica gel 60 Art number 9385.

Biotage refers to prepacked silica gel cartridges containing KP-Sil runon flash 12i chromatography module.

Bond Elut are prepacked cartridges used in parallel purifications,normally under vacuum. These are commercially available from Varian.

LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% HCO₂H and 0.01M ammonium acetate in water (solvent A),and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using thefollowing elution gradient 0–0.7 min 0% B, 0.7–4.2 min 100% B, 4.2–5.3min 0% B, 5.3–5.5 min 0% B at 3 ml/min. The mass spectra were recordedon a Fisons VG Platform spectrometer using electrospray positive andnegative mode (ES+ve and ES−ve).

HPLC was conducted on a LCABZ+PLUS column (3.3 cm×4.6 mm ID) elufingwith 0.1% formic acid and 0.01M ammonium acetate in water (solvent A),and 0.05% formic acid 5% water in acetonitrile (solvent B) using thefollowing elution gradient 0–1 min 0% B, 1–10 min 100% B, 10–13 min 100%B, 13–15 min 0% B at a flow rate of 1 ml/min detecting at 215 to 330 nm.

EXAMPLE 13-[3-(4-{[6-([(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

i) 6-Bromohexyl but-3-ynyl ether

3-Butyn-1-ol (42.4 ml) was stirred vigorously with 1,6-dibromohexane(260 ml) and tetrabutylammonium bisulphate (2.4 g) in 50% aqueous sodiumhydroxide solution (200 ml) under nitrogen for 3 days. Water (ca 700 ml)was added and the organic layer was separated. The aqueous layer wasextracted twice with dichloromethane (2×100 ml) and the combined organiclayers were washed with water, dried (MgSO₄) and concentrated. Theresidue in petroleum ether (bp 40–60°) was loaded onto a column ofsilica gel (1.5 kg) and the column was eluted with petroleum ether (bp40–60°), then 10% diethyl ether in petroleum ether (bp 40–60°) to givethe title compound (103.3 g).

ii) 1-{4-[(6-Bromohexyl)oxy]but-1-ynyl}-3-nitrobenzene

A mixture of 1-iodo-3-nitrobenzene (3 g), 6-bromohexyl but-3-ynyl ether(3 g), bis(triphenylphosphine)palladium (II) chloride (0.421 g), copper(I) iodide (0.114 g) in DMF (10 ml) and diisopropylethylamine (4 ml) wasstirred under nitrogen at 20° C. for 5 h. The mixture was concentratedunder reduced pressure and the residue was diluted in EtOAc and washedwith 2M HCl, NaHCO₃, brine and dried (MgSO₄). The solvent was removed byevaporation and the residue was chromatographed on a Biotage columneluting with ether:petroleum ether(40–60° C.) (1:9) to give the titlecompound (4.12 g). LCMS RT=4.14 min

iii) 6-{[4-(3-Nitrophenyl)but-3-ynyl]oxy}hexyl acetate

A mixture of 1-{4-[(6-bromohexyl)oxy]but-1-ynyl}-3-nitrobenzene (4.18g), sodium acetate (9.68 g), tetrabutylammonium bromide (384 mg) in DMF(15 ml) and water (10 ml) was heated to 75° C. for 6 h. The mixture wasthen allowed to cool to 20° C. and then extracted with Et₂O. The organicsolution was concentrated and purified by chromatography on a Biotage(40 g) eluting with Et₂O-petroleum ether(1:19 increasing to 1:1) to givethe title compound (2.973 g). LCMS RT=3.84 min.

iv) 6-[4-(3-Aminophenyl)butoxy]hexyl acetate

6-{[4-(3-Nitrophenyl)but-3-ynyl]oxy}hexyl acetate (2.973 g) washydrogenated over PtO₂ (300 mg) in EtOH over 1 h. The catalyst wasremoved by filtration and washed with EtOH. The combined filtrate andwashings were concentrated under reduced pressure to give the titlecompound (2.844 g) LCMS RT=3.30 min.

v) EthylN-({[3-(4-{[6-(acetyloxy)hexyl]oxy}butyl)phenyl]amino}carbonyl)glycinate

6-[4-(3-Aminophenyl)butoxy]hexyl acetate (2.84 g) in CH₂Cl₂ (30 ml) wastreated with ethyl isocyanatoacetate (1.2 ml). After 0.75 h the mixturewas treated with MeOH (2 ml) and stirred for 0.5 h. The mixture wasconcentrated, purified on a 10 g silica Bond Elut cartridge eluting withEt₂O-petroleum ether(1:1) and then with Et₂O to give the title compound(3.33 g) ES+ve 437 (MH)⁺.

vi) 3-(3-{4-[(6-Hydroxyhexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione

A solution of ethylN-({[3-(4-{[6-(acetyloxy)hexyl]oxy}butyl)phenyl]amino}-carbonyl)glycinate(2.967 g) in ethanol (30 ml) was treated under nitrogen with sodiumhydride (60% oil dispersion; 280 mg) and the mixture was stirred for 18h. The solvent was removed under reduced pressure, the residue wasdissolved in acetic acid (10 ml) and conc. HBr (1 ml) and the mixturewas heated to 75° C. for 1 h. The solvent was removed under reducedpressure, the residue was partitioned between EtOAc and brine. Theorganic solution was washed with brine, dried and evaporated to dryness.The residue was dissolved in MeOH (30 ml), SOCl₂ (0.5 ml) was added, andthe solution was stirred for 2 h. The solvent was removed under reducedpressure to give the title compound (2.67 g) ES+ve 349 (MH)⁺.

vii) 6-{4-[3-(2,5-Dioxoimidazolidin-1-yl)phenyl]butoxy}hexylmethanesulfonate

3-(3-{4-[(6-Hydroxyhexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione (2.67g) in CH₂Cl₂ (50 ml) and triethylamine (1.2 ml) was treated withmethanesulfonyl chloride (1.22 ml) and the mixture was stirred at 20° C.for 1.5 h. The mixture was diluted with CH₂Cl₂ and washed with 2M HCl,NaHCO₃, dried and purified by chromatography on Biotage (40 g) elutingwith EtOAc-petroleum ether(1:1) and then with 2% MeOH—CH₂Cl₂ to give thetitle compound (1.186 g) ES+ve 427 (MH)⁺.

viii) 2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone

2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (Glaxo DE3513885, 1985) (52 g) in DMF (300 ml) was treated with sodium azide(12.24 g) and the mixture was stirred for 2 h at 20° C. The reactionmixture was diluted with EtOAc and washed with water and dried (MgSO₄).The solvent was removed under reduced pressure to give the titlecompound (39.11 g). TSP+ve 248(MH)⁺.

ix) (1R)-2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

(R)-Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolesolution in toluene (1M, 7.5 ml) was added to THF (75 ml) and thesolution was diluted to 0° C. Borane-THF complex (1M solution in THF,125 ml) was added and the mixture was stirred under nitrogen for 15 min.A solution of 2-azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone(24.7 g) in THF (250 ml) was added dropwise over 1.5 h at 5° C. Themixture was stirred for a further 1 h and then cautiously treated with2M HCl (100 ml). The reaction mixture was extracted with ether and theorganic layer was washed with 2M HCl, NaHCO₃, brine, dried (MgSO₄). Thesolvent was removed by evaporation and the residue was chromatographedon a Biotage column eluting with ether-petroleum ether(40–60° C.) (1:9;1:1) to give the title compound (16.99 g). ES+ve 250 (MH)⁺.

x) (1R)-2-Amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

(1R)-2-Azido-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (16.99 g)was hydrogenated over 10% Pd—C (1 g) in EtOH (300 ml). The catalyst wascollected by filtration, and washed with EtOH. The combined washingswere evaporated under reduced pressure and the residue was triturated inether to give the title compound (5.86 g). The mother liquors werechromatographed on a Biotage column eluting with toluene:EtOH:aqueousammonia (85:14:1) to give a further batch of the title compound (5.99g). LCMS RT=1.68 min, ES+ve 206 (MH—H₂O)⁺.

xi)3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione

A solution of 6-{4-[3-(2,5-dioxoimidazolidin-1-yl)phenyl]butoxy}hexylmethanesulfonate (766 mg) in DMF (8 ml) was treated withtetrabutylammonium bromide (578 mg) and(1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (544 mg)and the mixture was stirred at 20° C. for 3 d. The solvent was removedunder reduced pressure, the residue was dissolved in CH₂Cl₂, washed withwater and purified by chromatography on Biotage (40 g) eluting with 3%2M NH₃ in MeOH:CH₂Cl₂ to give the title compound (417 mg). ES+ve 554(MH)⁺.

xii)3-[3-(4-{[6-([(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

A solution of3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine2,4-dione(414 mg) in acetic acid (20 ml) and water (5 ml) was heated to 75° C.for 30 min before evaporating to dryness. The residue was purified bychromatography on Biotage (40 g) eluting with CH₂Cl₂:MeOH:2M NH₃ in MeOH(85:10:5). Appropriate fractions were combined and evaporated todryness. Acetone (10 ml) was added and the mixture was re-evaporatedunder reduced pressure to give the title compound (290 mg). LCMS RT=2.44min, ES+ve 514 (MH)⁺.

1H NMR (DMSO+D2O) 7.36 (1H, t, J 8 Hz), 7.28 (1H, br s), 7.20 (1H, d, J8 Hz), 7.10 (1H, s), 7.09 (1H, d, J 8 Hz), 7.04 (1H, dd, J 8, 2 Hz),6.73 (1H, d, J 8 Hz), 4.73 (1H, dd, J 5, 8 Hz), 4.45 (2H, s), 4.08 (2H,s), 3.33 and 3.30 (2H each, t, J 7 Hz), 2.98–2.90 (2H, m), 2.86 (2H, t,J 7 Hz), 2.59 (2H, t, J 7 Hz), 1.85 (3H, s), 1.62–1.4 (8H, m), 1.3–1.2(4H, m)

EXAMPLE 23-[3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)phenyl]imidazolidine-2,4-dioneacetate

i) 1-{3-[(7-Bromoheptyl)oxy]prop-1-ynyl}-3-nitrobenzene

was prepared using methods similar to those described in Example 1ii).tlc Rf 0.21 (5% Et₂O/petrol)

ii) 7-{[3-(3-Nitrophenyl)prop-2-ynyl]oxy}heptyl acetate

was prepared using methods similar to those described in Example 1iii).LCMS RT=3.78 min

iii) 7-[3-(3-Aminophenyl)propoxy]heptyl acetate

was prepared using methods similar to those described in Example 1iv).LCMS RT=3.38 min

iv) EthylN-({[3-(3-{[7-(acetyloxy)heptyl]oxy}propyl)phenyl]amino}carbonyl)glycinate

was prepared using methods similar to those described in Example 1v).LCMS RT=3.52 min

v) 3-(3-{3-[(7-Hydroxyheptyl)oxy]propyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 1vi).ES+ve 349 (MH)⁺.

vi) 7-{3-[3-(2,5-dioxoimidazolidin-1-yl)phenyl]propoxy}heptylmethanesulfonate was prepared using methods similar to those describedin Example 1vii). ES+ve 427 (MH)⁺.

vii)3-(3-{3-[(7-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}phenyl)imidazolidine-2,4-dioneformate

was prepared using methods similar to those described in Example 1xi).ES+ve 554 (MH)⁺.

viii)3-[3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)phenyl]imidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xii).LCMS RT=2.39 min, ES+ve 514 (MH)⁺.

EXAMPLE 31-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2-oneacetate

i)Di(tert-butyl)2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate

Caesium carbonate (70.4 g) was added to a stirred suspension of2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone, (Glaxo, DE3513885, 1985) (61.8 g) and di-t-butyl iminodicarboxylate (47.15 g) inacetonitrile (600 ml) under nitrogen. After vigorous stirring at 21° for24 h the mixture was diluted with water (ca800 ml) and the product wasextracted with diethyl ether (1 litre, then 200 ml). The combinedorganic layers were washed with brine, dried (MgSO₄) and concentrated toca400 ml. The white crystals were collected by filtration, washed withdiethyl ether and dried to give the title compound (24.4 g) δ (CDCl₃)7.78(1H, dd, J 8, 2 Hz), 7.65 (1H, brs), 6.87(1H, d, J 8 Hz), 4.97(2H,s), 4.88(2H, s), 1.56(6H, s) and 1.48(18H, s). Further concentration ofthe mother liquors gave additional product (13.8 g). A third crop (7.1g) was obtained by chromatographing the mother liquors on silica gel,evaporating the appropriate eluate and triturating with diethyl ether.

ii) tert-Butyl2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate

Trifluoroacetic acid (92 ml) was added to a stirred solution ofdi(tert-butyl)2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate,(352.55 g) in dichloromethane (3.6 litres) at 21° and the reaction wasstirred for 1.5 h. Aqueous NaOH solution (1.75 litres) was added andafter 10 min the phases were separated. The organic layer was washedwith water, dried (MgSO₄) and evaporated to an oil. This was storedunder high vacuum overnight and then triturated with hexane:ether (3:1)to give the crude product (226.61 g). This was purified byrecrystallisation from diethyl ether to give the title compound (122.78g). Further product (61.5 g) was obtained from the mother liquors byevaporation and chromatography on a Biotage using 15% ethyl acetate inhexane. LCMS RT=3.37 min.

iii) tert-Butyl(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate

A 2M solution of borane—dimethyl sulphide in THF (28 ml) was addedslowly to a 1M solution of(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborolein toluene (56 ml) at 0° under nitrogen. A solution of tert-butyl2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate, (108.2 g)in THF (1.3 litres) was added slowly keeping the temperature below 5°followed by 2M solution of borane—dimethyl sulphide in THF (252 ml) over50 min. After 1 h, 2M HCl (170 ml) was added with cooling and themixture was partitioned between ethyl acetate and water. The organiclayer was washed with saturated NaHCO₃ solution and brine and dried(MgSO₄). The solution was concentrated and the product purified bychromatography on flash silica gel (800 g), eluting successively withhexane:ethyl acetate (4:1 then 3:1) to give the title compound (93.3 g),LCMS RT=3.31 min.

iv) (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

tert-Butyl(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate,(86.37 g) in DMF (600 ml) was added dropwise to a stirred suspension ofsodium hydride (60% oil dispersion, 11.9 g) in DMF (160 ml) with coolingsuch that the internal temperature remained at 0° under nitrogen. Themixture was stirred at 21° for 2 h. The mixture was recooled to 0° and2M HCl (134 ml) was added. The mixture was diluted with water and theproduct was extracted with ethyl acetate twice. The solution was washedwith brine twice, dried (MgSO₄) and evaporated to give the titlecompound (63.55 g) LCMS RT=2.66 min.

v) 6-Bromohexyl but-3-ynyl ether

was prepared as described in Example 1(i).

vi)(5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one

(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (10g) in DMF (100 ml) was added dropwise to a stirred suspension of sodiumhydride (60% oil dispersion, 2.33 g) in DMF (50 ml) with stirring undernitrogen and maintaining the internal temperature at 0°. Stirring wascontinued at 0–5° for 1 h. The mixture was recooled to 0° and a solutionof 6-bromohexyl but-3-ynyl ether (14.7 g) in DMF (50 ml) was added over1 min. The mixture was then stirred at 20–30° for 2 h. 2M HCl (9 ml) wasadded and the mixture was partitioned between water and diethyl ether.The aqueous layer was extracted with more diethyl ether and the combinedorganic layers were washed twice with brine. After drying (MgSO₄) thesolution was concentrated and loaded onto a column of silica gel (600 g)set up in diethyl ether: petroleum ether (bp 40–60°) (1:2). The columnwas eluted successively with this mixture, then (1:1) and then diethylether to give the title compound (13.88 g) LCMS RT=3.45 min.

vii) 1-(3-Iodophenyl)imidazolidin-2-one

A solution of 3-iodoaniline (1 g) in CH₂Cl₂ (5 ml) anddiisopropylethylamine (2 ml) was treated with 2-chloroethylisocyanate(0.4 ml) and the mixture was stirred at 20° C. for 3 d. The mixture wasdiluted with EtOAc and washed with 2M HCl, dried and evaporated todryness. The residue was dissolved in DMF (5 ml), treated with sodiumhydride (60% oil dispersion, 182 mg), and the mixture was stirred for 20h under nitrogen. The mixture was diluted with EtOAc, washed with 2MHCl, brine, dried and evaporated to dryness. The residue wascrystallised from hot EtOAc/MeOH. Trituration in Et₂O of the residueobtained by evaporation of the mother liquor gave the title compound(240 mg). LCMS RT=3.03 min.

viii)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-({4-[3-(2-oxoimidazolidin-1-yl)phenyl]but-3-ynyl}oxy)hexyl]-1,3-oxazolidin-2-one

(5R)-3-[6-(But-3-ynyloxy)hexyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one(376 mg) was stirred with 1-(3-iodophenyl)imidazolidin-2-one (250 mg) inDMF (10 ml) and diisopropylethylamine (3 ml) under nitrogen for 10 min.

Dichlorobis(triphenylphosphine)palladium (30 mg) and cuprous iodide (8mg) were added and the mixture was stirred for 17 h under nitrogen at20° C. The mixture was evaporated to dryness and the residue waschromatographed on Biotage (40 g) eluting with EtOAc-petroleum ether (bp40–60° C.) (1:1) and then on two preparative plates (20×20 cm) elutingwith MeOH—CH₂Cl₂ (1:19) to give the title compound (120 mg). LCMSRT=3.49 min

ix)(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(2-oxoimidazolidin-1-yl)phenyl]butoxyl{hexyl)-1,3-oxazolidin-2one

(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-({4-[3-(2-oxoimidazolidin-1-yl)phenyl]but-3-ynyl}oxy)hexyl]-1,3-oxazolidin-2-one(120 mg) was hydrogenated over platinum oxide (54 mg) in EtOH (100 ml).The catalyst was removed by filtration and the residue was leached withEtOH. The combined filtrates were evaporated under reduced pressure togive the title compound (113 mg). LCMS RT=3.55 min

x)1-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidin-2-one

(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-(6-{4-[3-(2-oxoimidazolidin-1-yl)phenyl]butoxy}hexyl)-1,3-oxazolidin-2-one(113 mg) was stirred in THF (8 ml) while purging with a vigorous streamof nitrogen for 3 min. Potassium trimethylsilanolate (285 mg) was addedand the mixture was stirred at 80° C. under nitrogen for 0.75 h. MeOH(10 ml) was added and then the solvents were removed under reducedpressure. The residue was dissolved in MeOH and applied to a silica BondElut cartridge (10 g) which was preconditioned in CH₂Cl₂ eluting withCH₂Cl₂, 5% MeOH—CH₂Cl₂, 2% increasing to 10% 2M NH₃ in MeOH—CH₂Cl₂ togive the title compound (39 mg). LCMS RT=2.94 min

xi)1-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidin-2-oneacetate

was prepared using methods similar to those described in Example 1xii).LCMS RT=2.47 min, ES+ve 500 (MH)⁺

EXAMPLE 41-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneformate

i) 1-(3-Iodophenyl)imidazolidine-2,4-dione

A solution of 3-iodophenylurea (2.1 g) in DMF (20 ml) was treated withsodium hydride (60% oil dispersion; 640 mg), followed by ethylchloroacetate (0.93 ml) and the mixture was stirred for 5 h. The mixturewas partitioned between EtOAc and 2M HCl and the organic solution waswashed with NaHCO₃, brine, dried and evaporated to dryness to give thetitle compound (2.08 g) ES+ve 303(MH)⁺.

ii)1-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 3vi).LCMS RT=3.63 min

iii)1-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 3vii).LCMS RT=3.53 min

iv)1-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 3viii).LCMS RT=2.98 min

v)1-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneformate

was prepared using methods similar to those described in Example 1xii).The crude product was purified on HPLC eluting with a gradient ofMeCN—H₂O—HCO₂H to give the title compound. LCMS RT=2.53 min, ES+ve 514(MH)⁺.

EXAMPLE 53-[3-(4-{[6-([(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

i) Ethyl N-{[(3-iodophenyl)amino]carbonyl}glycinate

A solution of 3-iodoaniline (9.39 g) in dichloromethane (75 ml) wastreated with ethyl isocyanatoacetate (7.21 ml) at 0° C. and the mixturewas stirred for 2 h and allowed to warm to 20° C. EtOH (10 ml) was addedand the mixture was stirred for 15 h. The solvents were evaporated underreduced pressure and the residue was triturated in Et₂O to give thetitle compound (12.9 g)LCMS RT=3.08 min.

ii) 3-(3-Iodophenyl)imidazolidine-2,4-dione

A solution of ethyl N-{[(3-iodophenyl)amino]carbonyl}glycinate (9.42 g)in DMF (60 ml) was treated with sodium hydride (60% oil dispersion, 1.2g) at 20° C. After 2 h the reaction mixture was treated with aqueous 2MHCl (200 ml) and stirred overnight. The solid was collected byfiltration, washed with water and dried to give the title compound (6.9g) LCMS RT=2.45 min.

iii)3-(3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

A mixture of 3-(3-iodophenyl)imidazolidine-2,4-dione (0.75 g),6-bromohexyl but-3-ynyl ether (1.3 g), bis(triphenylphosphine)palladiumdichloride (87 mg) in DMF (10 ml) was treated with diisopropylethylamine(3 ml) and copper (I) iodide (23 mg) and the mixture was stirred forunder nitrogen for 24 h. The solvents were removed under reducedpressure, the residue was diluted with EtOAc and washed with aqueous 2MHCl, aqueous dilute ammonia, brine and dried (MgSO₄). The solvent wasremoved under reduced pressure and the residue was purified on two BondElut 10 g silica cartridges eluting with dichloromethane, Et₂O, andEtOAc to give the title compound (760 mg) together with3-(3-{4-[(6-iodohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione (760mg, 22:3).

iv)3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

A mixture of3-(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione and3-(3-{4-[(6-iodohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione (760mg, 22:3), (1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol(800 mg) in DMF (5 ml) was stirred at 20° C. for 22 h. The solvent wasremoved under reduced pressure and the residue was diluted with EtOAcand washed with water, brine and dried (MgSO₄). The solution wasconcentrated and purified by chromatography on Biotage (40 g) elutingwith dichloromethane:MeOH:1M ammonia in methanol (98:1:1 to 95:4:1) togive the title compound (368 mg) LCMS RT=2.59 min.

v)3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}imidazolidine-2,4-dione

A solution of3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione(368 mg) was hydrogenated over platinum oxide (100 mg) in EtOAc (100 ml)over 3 h. The catalyst was collected by filtration, washed with EtOAcand EtOH. The combined filtrate and washings were evaporated underreduced pressure to give the title compound LCMS RT=2.55 min

vi)3-[3-(4-{[6-([(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xiiLCMS RT=2.38 min, ES+ve 514(MH)⁺.

EXAMPLE 63-[3-(4-{[6-([(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

(i) (1R) 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

A solution R-diphenylprolinol (75 mg) in THF (2 ml) was treated withborane-THF (1M, 20.5 ml) over 20 min at 20° C. under nitrogen. After theaddition was complete the solution was kept between 30 and 35° C. for 1h and then cooled in ice and2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (DE3513885)(3.9 g) in THF (10 ml) was added over 1.5 h keeping the temperaturebelow 5° C. The mixture was stirred under nitrogen for a further 0.5 hand then methanol (4 ml) was added at 0° C. The solvent was removedunder reduced pressure and the residue was purified by chromatography onflash silica gel eluting with ethyl acetate-cyclohexane (1:4) to givethe title compound (3.31 g) δ (CDCl₃) 7.15 (1H, dd, J 8, 2 Hz), 7.03(1H, br s), 6.82 (1H, d, J 8 Hz), 4.85 (3H, s and m), 3.61 (1H, dd, J10, 4 Hz), 3.50 (1H, dd, J 10, 9 Hz), 1.54 (6H, s).

(ii){[(1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethyl]oxy}(triethyl)silane

Triethylsilyl chloride (205 g) was added dropwise to a stirred mixtureof (1R)-2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (350 g)and imidazole (108.5 g) in DMF (875 ml) at 5° C. Upon complete additionthe mixture was warmed to 15° C. and stirred, at this temperature for 1h. n-Hexane (3500 ml) was then added to the mixture which was washedwith water (3×1750 ml). The organic layer was dried over anhydrous MgSO₄before being filtered and concentrated under reduced pressure to givethe title compound (488.6 g) as an oil, δ (DMSO-d₆) 7.18 (1H, d, J 8.2Hz), 7.10 (1H, s), 6.75 (1H, d, J 8.2 Hz), 4.83 (1H, m), 4.78 (2H, d, J6.9 Hz), 3.55 (2H, m), 1.45 (6H, s), 0.84 (9H, t, J 8.1 Hz), 0.51 (6H,m).

iii)N-Benzyl-N-{(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(triethylsilyl)oxy]ethyl}amine

A mixture of{[(1R)-2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethyl]oxy}(triethyl)silane(130 g) and benzylamine (177 ml) in 1,4-dioxane (650 ml) was heated at105° C. with stirring overnight. The mixture was then cooled to roomtemperature and water (150 ml) and diethyl ether (1200 ml) added. Thelayers were separated and the ethereal layer was washed with saturatedammonium chloride solution (3×600 ml), saturated sodium bicarbonatesolution (200 ml) and then brine (200 ml). The solution was dried overanhydrous Na₂SO₄ before being filtered and concentrated under reducedpressure to give the title compound (129.9 g) as an oil, δ (CDCl₃) 7.22(5H, m), 7.02 (1H, d, J 8.7 Hz), 6.86 (1H, s), 6.68 (1H, d, J 8.3 Hz),4.75 (2H, s), 4.69 (1H, m), 3.73 (2H, s), 2.70 (2H, m), 1.46 (6H, s),0.79 (9H, m), 0.44 (6H, m).

iv) (1R)-2-(Benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

Tetrabutylammonium fluoride (395 ml, 1M in THF) was added dropwise to astirred solution ofN-benzyl-N-{(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(triethylsilyl)oxy]ethyl}amine(129.9 g) in THF (900 ml) at 5° C. Upon complete addition the reactionmixture was maintained at this temperature for 15 min before water (600ml) was added. The resulting slurry was diluted with diethyl ether (500ml) and filtered. The filtrate was washed with water (2×500 ml) andbrine (500 ml) before being dried over anhydrous Na₂SO₄. The resultingmixture was filtered and concentrated under reduced pressure to give asolid which was triturated with diisopropyl ether to give the titlecompound (70 g) as a solid, δ (CDCl₃) 7.31 (5H, m), 7.09 (1H, d, J 8Hz), 6.98 (1H, s), 6.77 (1H, d J 8 Hz), 4.82 (2H, s), 4.63 (1H, m), 3.83(2H, d, J 4 Hz), 2.80 (2H, m), 1.52 (6H, s).

v)3-(3-{4-[(6-{Benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

A solution of3-(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione and3-(3-{4-[(6-iodohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione(3:1, 23.98 g) in acetonitrile (240 ml) and diisopropylethylamine (20ml) was treated with(1R)-2-(benzylamino)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol(18.22 g) and the mixture was heated to 50° C. for 5 days. The solventwas removed under reduced pressure, the residue was diluted with EtOAc(250 ml) and washed with water. The aqueous phase was re-extracted withEtOAc (75 ml) and the combined organic solutions were washed with brine,dried (MgSO₄), and evaporated. The residue was purified bychromatography on flash silica gel eluting with dichloromethane-EtOAc(1:1) to give the title compound (17.25 g) LCMS RT=2.80 min

vi)3-[3-(4-{[6-([(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione

A solution of3-(3-{4-[(6-{benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione(9.05 g) in a mixture of isopropanol-EtOAc (9:1, 200 ml) washydrogenated over Pearlman's catalyst (1.8 g). After 2 days aqueous 2MHCl (10 ml) was added and the mixture was hydrogenated for a further 2h. The catalyst was removed by filtration and the filtrate wasconcentrated under reduced pressure. The residue was purified bychromatography on Biotage eluting with dichloromethane-isopropanol-880ammonia (34:7:1) to give the title compound (2.8 g) LCMS RT=2.34 minES+ve 514 (MH)⁺.

EXAMPLE 73-[3-(4-{[6-([(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

i) 6-(But-3-ynyloxy)hexanal

6-Bromohexylbut-3-ynyl ether (525 mg) in DMSO (2 ml) was added to amixture of sodium bicarbonate (1 g) in DMSO (8 ml) at 150° C. withvigorous stirring and nitrogen bubbling through the solution. Themixture was stirred for 20 min at 150° C. and then allowed to cool toroom temperature, diluted with Et₂O and washed with water. The aqueouslayer was extracted with Et₂O and the combined ether layers were washedwith dilute hydrochloric acid, brine, dried (MgSO₄) and evaporated todryness to give the title compound (325 mg): IR 1726 cm⁻¹ MS(TSP+ve) m/z186 (M+MH₄)⁺.

ii)(1R)-2-{[6-(But-3-ynyloxy)hexyl][(1S)-2-hydroxy-1-phenylethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol

A mixture of 6-(but-3-ynyloxy)hexanal (434 mg) and(1R)-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S)-2-hydroxy-1-phenylethyl]amino}ethanol(WO0196278 A2) (710 mg) in chloroform (10 ml) was treated at 20° C. withsodium triacetoxyborohydride (866 mg) and stirred under nitrogen for 2days. The mixture was diluted with EtOAc and aqueous sodium bicarbonatesolution. The organic phase was separated and washed with sodiumbicarbonate solution, brine, dried and purified on a silica Bond Elutcartridge (10 g) eluting with dichloromethane, Et₂O and finally EtOAc togive the title compound (810 mg): LCMS RT=2.69 min, ES+ve m/z 496(M+H)⁺.

iii)3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl][(1S)-2-hydroxy-1-phenylethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 1iiLCMS RT=2.82 min, ES+ve 670 (MH)⁺.

iv)3-[3-(4-{[6-([(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 6(vi)LCMS RT=2.39 min, ES+ve 514 (MH)⁺.

EXAMPLE 83-[3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

i)3-(3-{4-[(6-{[(2S)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5ivfrom (1S)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol(Tetrahedron:Asymmetry 2001, 12, 2005).

ii)3-(3-{4-[(6-{[(2S)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5v.

iii)3-[3-(4-{[6-({(2S)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xii.

EXAMPLE 93-[4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

i) Ethyl N-{[(4-iodophenyl)amino]carbonyl}glycinate

was prepared using method similar to those described in Example 5i. LCMSRT=3.1 min.

ii) 3-(4-Iodophenyl)imidazolidine-2,4-dione

was prepared using method similar to those described in Example 5ii.LCMS RT=2.49 min.

iii)3-(4-{4-[(6-Bromohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using method similar to those described in Example 5iii.LCMS RT=3.46 min.

iv)3-(4-{4-[(6-{[(2R-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using method similar to those described in Example 5iv.LCMS RT=2.58 min.

v)3-(4-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione

was prepared using method similar to those described in Example 5v. LCMSRT=2.55 min.

vi)3-[4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

was prepared using method similar to those described in Example 1xii.LCMS RT=2.34 min, ES+ve 514(MH)⁺.

EXAMPLE 103-[2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

i) Ethyl N-{[(2-iodophenyl)amino]carbonyl}glycinate

was prepared using method similar to those described in Example 5i. LCMSRT=2.62 min.

ii) 3-(2-Iodophenyl)imidazolidine-2,4-dione

A solution of ethyl N-{[(2-iodophenyl)amino]carbonyl}glycinate (6 g) inMeOH was treated with aqueous NaOH (2M, 17.5 ml) and stirred undernitrogen for 0.5 h at 20° C. The reaction mixture was quenched by addingaqueous 2M HCl (20 ml) and water. The white solid obtained was collectedby filtration and then was dissolved in dioxane (30 ml) and treated withp-toluenesulfonic acid (750 mg). The mixture was heated and stirred at100° C. for 16 h. The solvent was removed under reduced pressure, theresidue was diluted in EtOAc and washed with water, brine and dried(MgSO₄). The solvent was removed under reduced pressure and the residuewas purified by chromatography on Biotage (40 g) eluting withdichloromethane:EtOAc (95:5 to 85:15) to give the title compound (1.68g). LCMS RT=2.07 min.

iii)3-(2-{4-[(6-Bromohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iii.LCMS RT=3.29 min.

iv)3-(2-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using method similar to those described in Example 5iv.LCMS RT=2.48 min.

v)3-(2-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5v.LCMS RT=2.42 min.

vi)3-[2-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

was prepared using method similar to those described in Example 1xii.LCMS RT=2.08 min, ES+ve 514(MH)⁺.

EXAMPLE 113-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]imidazolidine-2,4-dioneacetate

i) Ethyl N-{[(3-iodobenzyl)amino]carbonyl}glycinate

was prepared using methods similar to those described in Example 5i.LCMS RT=2.71 min.

ii) 3-(3-Iodobenzyl)imidazolidine-2,4-dione

A solution of ethyl N-{[(3-iodobenzyl)amino]carbonyl}glycinate (7.6 g)in MeOH (40 ml) was treated with aqueous 2M NaOH (21.2 ml) and stirredunder nitrogen at 20° C. The mixture crushed out instantly and wasquenched by adding aqueous 2M HCl (22 ml). The residue was filtered togive the title compound (4.4 g) LCMS=2.73 min.

iii)3-(3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}benzyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iii.LCMS RT=3.35 min.

iv)3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}benzyl)imidazolidine-2,4-dione

was prepared using method similar to those described in Example 5iv.LCMS RT=2.52 min.

v)3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzyl)imidazolidine-2,4-dione

was prepared using method similar to those described in Example 5v. LCMSRT=2.70 min.

vi)3-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]imidazolidine-2,4-dioneacetate

was prepared using method similar to those described in Example 1xii.LCMS RT=2.44 min, ES+ve 528(MH)⁺.

EXAMPLE 123-[3-(5-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}pentyl)phenyl]imidazolidine-2,4-dioneacetate

i) 5-[(5-Bromopentyl)oxy]pent-1-yne

was prepared using methods similar to those described in Example 1i.LCMS RT=3.62 min.

ii) 5-Bromopentyl 5-(3-nitrophenyl)pent-4-ynyl ether

was prepared using methods similar to those described in Example 1ii.TLC Rf=0.18 (Et₂O-petroleum ether 1:19)

iii) 5-{[5-(3-Nitrophenyl)pent-4-ynyl]oxy}pentyl acetate

was prepared using methods similar to those described in Example 1iii.LCMS RT=3.69 min

iv) 5-{[5-(3-Aminophenyl)pentyl]oxy}pentyl acetate

was prepared using methods similar to those described in Example 1iv.LCMS RT=3.12 min

v) EthylN-({[3-(5-{[5-(acetyloxy)pentyl]oxy}pentyl)phenyl]amino}carbonyl)glycinate

was prepared using methods similar to those described in Example 1v.LCMS RT=3.45 min

vi) 3-(3-{5-[(5-(Hydroxypentyl)oxy]pentyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 1vi.LCMS RT=2.77 min

vii) 5-[(5-{3-[3-(2,5-Dioxoimidazolidin-1-yl)phenyl}pentyl)oxy]pentylmethanesulfonate

was prepared using methods similar to those described in Example 1vii.LCMS RT=3.05 min

viii) 3-(3-{5-[(5-Bromopentyl)oxy]pentyl}phenyl)imidazolidine-2,4-dione

A solution of5-[(5-{3-[3-(2,5-dioxoimidazolidin-1-yl)]phenyl}pentyl)oxy]pentylmethanesulfonate (1.72 g) in acetonitrile (30 ml) was treated withtetrabutylammonium bromide (2.6 g) at 20° C. After two days moretetrabutylammonium bromide (1 g) was added and the mixture was stirredfor a further day. The solvent was removed under reduced pressure andthe residue was purified by chromatography on a Biotage cartridge (40 g)eluting with EtOAc-petroleum ether (1:2, 1:1) to give the title compound(754 mg) LCMS RT=3.36 min

ix)3-(3-{5-[(5-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}pentyl)oxy]pentyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 1xiLCMS RT=2.48 min

x)3-[3-(5-{[5-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)pentyl]oxy}pentyl)phenyl]imidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xiiLCMS RT=2.22 min, ES+ve 514 (MH)⁺.

EXAMPLE 133-[3-(5-{[6-(}(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}pentyl)phenyl]imidazolidine-2,4-dioneacetate

i) 5-[(6-Bromohexyl)oxy]pent-1-yne

was prepared using methods similar to those described in Example 1i.GCMS RT=5.6 min

ii) 3-(3-{5-[(6Bromohexyl)oxy]pent-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iiiLCMS RT=3.57 min

iii)3-(3-{5-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6yl)-2-hydroxyethyl]amino}hexyl)oxy]pent-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5ivLCMS RT=2.54 min

iv)3-(3-{5-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]pentyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5v LCMSRT=2.71 min

v)3-[3-(5-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}pentyl)phenyl]imidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xiiLCMS RT=2.47 min, ES+ve 528 (MH)⁺.

EXAMPLE 143-[3-(6-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}hexyl)phenyl]imidazolidine-2,4-dioneacetate

i) 6-[(6-Bromohexyl)oxy]hex-1-yne

was prepared using methods similar to those described in Example 1i.GCMS RT=5.99 min

ii) 3-(3-Iodophenyl)imidazolidine-2,4-dione

was prepared using method similar to those described in Example 5ii.LCMS RT=2.54 min.

iii)3-(3-{6-[(6-Bromohexyl)oxy]hex-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iii.LCMS RT=3.55 min.

iv)3-(3-{6-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]hex-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using method similar to those described in Example 5iv.LCMS RT=2.68 min.

v)3-(3-{6-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]hexyl}phenyl)imidazolidine-2,4-dione

was prepared using method similar to those described in Example 5v. LCMSRT=2.73 min.

vi)3-[3-(6-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}hexyl)phenyl]imidazolidine-2,4-dioneacetate

was prepared using method similar to those described in Example 1xii.LCMS RT=2.81 min, ES+ve 582(MH)⁺.

EXAMPLE 15(5R)-5-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-5-methylimidazolidine-2,4-dioneacetate

i) Benzyl(2S,4R)-4-(3-iodobenzyl)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate

A solution of benzyl(2S,4S)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate (J. Org.Chem. 2001, 66, 1903) (1.2 g) and 3-iodobenzyl bromide (1.15 g) in THF(8 ml) was added dropwise to a solution of lithium hexamethyldisilazanein THF (1M, 4.1 ml) diluted in THF (32 ml) at −30° C. The mixture wasstirred at this temperature and then allowed to warm to 20° C. over 4 h.Aqueous sodium bicarbonate solution was then added and the mixture wasextracted with Et₂O. The organic phase was separated and dried (MgSO₄),filtered and evaporated. The residue was purified by chromatography on aBiotage cartridge (40 g) eluting with EtOAc-petroleum ether (1:9, 1:4)to give the title compound (1.48 g) HPLC RT=9.33 min.

ii) 3-Iodo-α-methyl-D-phenylalanine

A mixture of benzyl(2S,4R)-4-(3-iodobenzyl)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate(1.47 g) and potassium trimethylsilanolate (1.2 g) was suspended in THF(50 ml) and heated to 75° C. for 2.5 h. MeOH (10 ml) was added and thesolvents were removed under reduced pressure. The residue was dissolvedin MeOH and applied to two 10 g SCX-2 cartridges eluting with MeOH andthen with 0.2M ammonia in MeOH. The ammoniacal solutions were evaporatedto dryness to give the title compound (910 mg) LCMS RT=1.93 min.

iii) Methyl 3-iodo-α-methyl-D-phenylalaninate

A solution of 3-iodo-α-methyl-D-phenylalanine (0.9 g) in MeOH (50 ml)was treated with thionyl chloride (3.5 ml) and the mixture was heated toreflux for 3 days. The solvent was removed under reduced pressure andthe residue was dissolved in EtOAc and washed with aqueous sodiumbicarbonate, brine, dried (MgSO₄) and evaporated to dryness to give thetitle compound (0.73 g) LCMS RT=2.12 min.

iv) Methyl N-(aminocarbonyl)-3-iodo-α-methyl-D-phenylalaninate

A mixture of methyl 3-iodo-α-methyl-D-phenylalaninate (0.73 g) in aceticacid (3 ml) and water (1 ml) was treated with sodium cyanate (0.4 g) andstirred for 2 days at 20° C. The solvents were removed under reducedpressure and the residue was diluted with EtOAc. The solution was washedwith water, brine, dried (MgSO₄) and evaporated to give the titlecompound (0.82 g) LCMS RT=2.74 min.

v) (5R)-5-(3-Iodobenzyl)-5-methylimidazolidine-2,4-dione

A mixture of methyl N-(aminocarbonyl)-3-iodo-α-methyl-D-phenylalaninate(0.82 g) and potassium carbonate (624 mg) in dimethyl sulfoxide (5 ml)was heated to 110° C. for 3 h and then allowed to cool to 20° C.overnight. The mixture was diluted with EtOAc and washed with 2M HCl,brine, dried (MgSO₄) and evaporated to dryness to give the titlecompound (521 mg) LCMS RT=2.61 min

vi)(5R)-5-(3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}benzyl)-5-methylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iiiLCMS RT=3.36 min

vii)(5R)-5-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}benzyl)-5-methylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5ivLCMS RT=2.58 min

viii)(5R)-5-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzyl)-5-methylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5v LCMSRT=2.69 min

ix)(5R)-5-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-5-methylimidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xiiLCMS RT=2.41 min, ES+ve 542(MH)⁺.

EXAMPLE 16(5S)-5-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-5-methylimidazolidine2,4-dioneacetate

i) Benzyl(2R,4S)-4-(3-iodobenzyl)-4-methyl-5-oxo-2-phenyl-1,3-oxazolidine-3-carboxylate

was prepared using methods similar to those described in Example 15iLCMS RT=3.98 min

ii) 3-Iodo-α-methyl-L-phenylalanine

was prepared using methods similar to those described in Example 15iiLCMS RT=2.03 min

iii) Methyl 3-iodo-α-methyl-L-phenylalaninate

was prepared using methods similar to those described in Example 15iiiLCMS RT=2.21 min

iv) Methyl N-(aminocarbonyl)-3-Iodo-α-methyl-L-phenylalaninate

was prepared using methods similar to those described in Example 15ivLCMS RT=2.78 min

v) (5S)-5-(3-Iodobenzyl)-5-methylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 15vLCMS RT=2.69 min

vi)(5S)-5-(3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}benzyl)-5methylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iiiLCMS RT=3.39 min

vii)(5S)-5-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}benzyl)-5-methylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5ivLCMS RT=2.63 min

viii)(5S)-5-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzyl)-5-methylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5v LCMSRT=2.65 min

ix)(5S)-5-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-5methylimidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xiiLCMS RT=2.37 min, ES+ve 542(MH)⁺.

EXAMPLE 172-{3-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,4-dioxoimidazolidin-1-yl}acetamideacetate

i) 2-[3-(3-Iodophenyl)-2,4-dioxoimidazolidin-1-yl]acetamide

A solution of 3-(3-iodophenyl)imidazolidine-2,4-dione (1 g) in DMF (20ml) was treated with sodium hydride (60% oil dispersion, 158 mg) and2-bromoacetamide (1.36 g) at 20° C. After 2 h the reaction mixture wastreated with aqueous 2M HCl, extracted with EtOAc and dried (MgSO₄). Thesolvent was removed under reduced pressure and the residue was purifiedby chromatography on Biotage (40 g) eluting with EtOAc to give the titlecompound (638 mg). LCMS RT=2.32 min.

ii)2-[3-(3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}phenyl)-2,4-dioxoimidazolidin-1-yl]acetamide

was prepared using methods similar to those described in Example 5iii.LCMS RT=3.17 min.

iii)2-[3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)-2,4-dioxoimidazolidin-1-yl]acetamide

was prepared using methods similar to those described in Example 5iv.LCMS RT=2.50 min.

iv)2-[3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-2,4-dioxoimidazolidin-1-yl]acetamide

was prepared using methods similar to those described in Example 5v.LCMS RT=2.59 min.

v)2-{3-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,4-dioxoimidazolidin-1-yl]-yl}acetamideacetate

was prepared using method similar to those described in Example 1xii.LCMS RT=2.23 min, ES+ve 571 (MH)⁺.

EXAMPLE 185-[4-(4-{[6-({(2)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]imidazolidine2,4-dionecompound with formic acid (1:1)

i) Methyl N-(aminocarbonyl)-4-iodo-L-phenylalaninate

was prepared using methods similar to those described in Example 15ivLCMS RT=2.78 min

ii) 5-(4-Iodobenzyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 15vLCMS RT=2.54 min

iii)5-{4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzyl}imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 3viiiLCMS RT=3.22 min

iv)5-{4-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzyl}imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 3ixLCMS RT=3.41 min

v)5-[4-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]imidazolidine-2,4-dionecompound with formic acid (1:1)

was prepared using methods similar to those described in Example 3x

EXAMPLE 191-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-1,3-dihydro-2H-imidazol-2-one

i) N-(2,2-Dimethoxyethyl)-N′-(3-iodophenyl)urea

A suspension of 3-iodophenylisocyanate (1.1 g) in DCM (10 ml) wastreated with aminoacetaldehyde dimethyl acetal (0.49 ml) and stirredunder nitrogen at 20° C. for 24 h. The reaction mixture was quenched byadding MeOH. The solvents were removed under reduced pressure to givethe title compound (1.35 g) LCMS RT=2.92 min.

ii) 1-(3-Iodophenyl)-1,3-dihydro-2H-imidazol-2-one

N(2,2-Dimethoxyethyl)-N′-(3-iodophenyl)urea (618 mg) was dissolved inacetic acid (10 ml) and water (1 ml) and the mixture was stirred at 20°C. for 17 h and then heated to 100° C. for 0.5 h. The solvent wasremoved under reduced pressure and the residue was dissolved in ethylacetate. The solution was washed with NaHCO₃ solution, dried andpurified by chromatography on 10 g silica Bond Elut cartridge elutingwith EtOAc-petroleum ether (1:7 to 1:1) to give the title compound (130mg) LCMS RT=2.66 min.

iii)1-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-1,3-dihydro-2H-imidazol-2-onemay be prepared using for example the methods described in Example 5iito 5vi. LCMS RT=2.28 min, ES+ve 498 (MH)⁺.

EXAMPLE 203-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-5,5-dimethylimidazolidine-2,4-dioneacetate

i) 3-(3-Iodophenyl)-5,5-dimethylimidazolidine-2,4-dione

BOC-α-methylalanine (1.01 g) and diisopropylethylamine (1.74 ml) indichloromethane (2 ml) was treated with tetramethylfluoroformamidiniumhexafluorophosphate (1.32 g) and the mixture was stirred for 18 h.3-Iodoaniline (1.09 g) in dichloromethane (2 ml) was added, followed bydiisopropylethylamine (1 ml). The mixture was stirred for 84 h and thenthe solvents were removed under reduced pressure. The residue waspartitioned between EtOAc and 2M HCl. The organic solution was washedwith 2M HCl, sodium bicarbonate solution, brine and dried (MgSO₄). Thefiltrate was concentrated and then triturated indichloromethane-cyclohexane (1:1, 20 ml) to give a solid (740 mg). Thesolution was purified by chromatography on two 10 g silica Bond Elutcartridges eluting with dichloromethane to give additional solid (633mg). LCMS RT=3.41 min. The solid (735 mg) was dissolved in DMF (3 ml)and then treated with sodium hydride (60% oil dispersion, 109 mg). Themixture was stirred overnight at room temperature and then heated to 75°C. for 3 h. The solvent was removed under reduced pressure and treatedwith 4M HCl in dioxane. The resulting solution was heated for 2 h at 75°C., concentrated, and the residue was triturated in Et₂O to give thetitle compound (487 mg). LCMS RT=2.79 min

ii)3-(3-{4-[(6-(Bromohexyl)oxy]but-1-ynyl}phenyl)-5,5-dimethylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iii.LCMS RT=3.51 min

iii)3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)-5,5-dimethylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iv.LCMS RT=2.72 min

iv)3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-5,5-dimethylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5v.LCMS RT=2.60 min

v)3-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-5,5-dimethylimidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xii.LCMS RT=2.47 min, ES+ve 542 (MH)⁺.

EXAMPLE 213-[3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)phenyl]-1-(methylsulfonyl)imidazolidine-2,4-dioneacetate

i)7-[(3-{3-[3-(methylsulfonyl)-2,5-dioxoimidazolidin-1-yl]phenyl}propyl)oxy]heptylmethanesulfonate

was prepared using methods similar to those described in Example 1vii.LCMS RT=2.80 min

ii)3-(3-{3-[(7-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}heptyl)oxy]propyl}phenyl)-1-(methylsulfonyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 1xi.LCMS RT=2.85 min

iii)3-[3-(3-{[7-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)phenyl]-1-(methylsulfonyl)imidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xii.LCMS RT=2.54 min, ES+ve 592 (MH)⁺.

EXAMPLE 221-[3-(3-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}propyl)phenyl]imidazolidine-2,4-dioneacetate

i)1-{3-[3-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)prop-1-ynyl]phenyl}imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 4ii.LCMS RT=3.43 min

ii)1-{3-[3-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)propyl]phenyl}imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 3ix.LCMS RT=3.42 min

iii)1-(3-{3-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino{hexyl)oxy]propyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 3x.LCMS RT=2.60 min

iv)1-[3-(3-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}propyl)phenyl}imidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xii.LCMS RT=2.34 min, ES+ve 500 (MH)⁺

EXAMPLE 23N-{1-[3-(4-{[6({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-2,5-dioxoimidazolidin-4-yl]ureaacetate

i) N-[1-(3-Iodobenzyl)-2,5-dioxoimidazolidin-4-yl]urea

Allantoin (1.58 g) was stirred with meta-iodobenzyl bromide (2.97 g) inDMF (25 ml) at 21° under nitrogen and sodium hydride (60% oildispersion; 0.40 g) was added over 5 min. After 2 h the solution waspartitioned between EtOAc and water and hydrochloric acid was added togive pH 3. The separated aqueous layer was extracted with more EtOAc andthe combined organic layers were washed with water and brine twice.After drying (MgSO₄), the solution was concentrated to 20 ml. After 1 hthe solid was collected by filtration and washed with EtOAc. The residuewas boiled with EtOAc (50 ml) and the slurry was allowed to cool. Thesolid was collected by filtration, washed with ethyl acetate and driedto give the title compound (0.507 g). LCMS RT=2.44 min

ii)N-[1-(3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}benzyl)-2,5-dioxoimidazolidin-4-yl]ureawas prepared using methods similar to those described in Example 5iii.LCMS RT=3.29 min

iii)N-[1-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}benzyl)-2,5-dioxoimidazolidin-4-yl]urea

was prepared using methods similar to those described in Example 5iv.LCMS RT=2.57 min

iv)N-[1-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzyl)-2,5-dioxoimidazolidin-4-yl]urea

was prepared using methods similar to those described in Example 5v.LCMS RT=2.61 min

v)N-{1-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-2,5-dioxoimidazolidin-4-yl]ureaacetate

was prepared using methods similar to those described in Example 1xii.LCMS RT=2.36 min, ES+ve 586 (MH)⁺

EXAMPLE 243-Benzyl-1-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl{amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

i) 3-Benzyl-1-(3-iodophenyl)imidazolidine-2,4-dione

1-(3-Iodophenyl)imidazolidine-2,4-dione (0.5 g) was taken up in dry DMF(10 ml) and treated with sodium hydride (60% oil dispersion, 73 mg) andstirred for 20 min under nitrogen. Benzyl bromide (0.295 ml) was addedand stirring continued for 3 h. 2M HCl (100 ml) was added and themixture extracted with EtOAc. The combined extracts were washed withsaturated aqueous sodium hydrogen carbonate (50 ml), brine (50 ml) anddried (MgSO₄). This was recrystallised from MeOH to give the titlecompound (0.255 g). LCMS RT 3.53 min.

ii)3-Benzyl-1-(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iii).LCMS RT=3.99 min

iii)3-Benzyl-1-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iv).LCMS RT=3.02 min

iv)3-Benzyl-1-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl]imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5v).LCMS RT=3.08 min

v)3-Benzyl-1-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenylethyl]amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xii).LCMS RT=2.81 min, ES+ve 604 (MH)⁺.

EXAMPLE 251-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-3-methylimidazolidine-2,4-dioneacetate

i) 1-(3-Iodophenyl)-3-methylimidazolidine-2,4-dione

1-(3-Iodophenyl)imidazolidine-2,4-dione (0.588 g) was suspended in water(13 ml) and treated with potassium hydroxide (0.37 g). The reaction wasplaced in a warming bath (45° C.) and treated with dimethyl sulfate(0.784 ml). After stirring for 4 h the reaction mixture was chilled andfiltered. The cake was washed with water and dried to give the titlecompound (0.381 g). LCMS RT=2.94 min.

ii)1-(3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}phenyl)-3-methylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iii).LCMS RT=3.64 min.

iii)1-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)-3-methylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iv).LCMS RT=2.79 min.

iv)1-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-3-methylimidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5v).LCMS RT=2.76 min.

v)1-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-3-methylimidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xii).LCMS RT=2.48 min, ES+ve 527 (MH)⁺.

EXAMPLE 26 Ethyl{3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,5-dioxoimidazolidin-1-yl}acetateacetate

i) Ethyl [3-(3-iodophenyl)-2,5-dioxoimidazolidin-1-yl]acetate

1-(3-Iodophenyl)imidazolidine-2,4-dione (0.5 g) was dissolved in dry DMF(10 ml) and treated with sodium hydride (60% oil dispersion, 73 mg) andstirred under nitrogen. After 20 min ethyl chloroacetate (0.255 ml) wasadded. After 3 h 2M HCl (100 ml) was added and the mixture extractedwith EtOAc. The combined extracts were dried (MgSO₄) and evaporatedunder reduced pressure. Trituration with di-tert-butyl ether (2×10 ml)gave the title compound (0.571 g). LCMS RT=3.21 min.

ii) Ethyl[3-(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)-2,5-dioxoimidazolidin-1-yl]acetate

was prepared using methods similar to those described in Example 5iii).LCMS RT=3.79 min.

iii) Ethyl[3-(3-{(4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)-2,5-dioxoimidazolidin-1-yl]acetate

was prepared using methods similar to those described in Example 5iv).LCMS RT=2.85 min.

iv) Ethyl[3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-2,5-dioxoimidazolidin-1-yl]acetate

was prepared using methods similar to those described in Example 5v).LCMS RT=2.93 min.

v) Ethyl{3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,5-dioxoimidazolidin-1-yl}acetateacetate

was prepared using methods similar to those described in Example 1xii).LCMS RT=2.65 min, ES+ve 600 (MH)⁺.

EXAMPLE 272-{3-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,5-dioxoimidazolidin-1-yl}acetamideacetate

i) 2-[3-(3-Iodophenyl)-2,5-dioxoimidazolidin-1-yl]acetamide

1-(3-Iodophenyl)imidazolidine-2,4-dione (0.302 g) was taken up in dryDMF (15 ml) and treated with bromoacetamide (0.399 g) and then withsodium hydride (60% oil dispersion, 48 mg). After 3 h pH 6.4 phosphatebuffer (50 ml) was added and the reaction mixture extracted with EtOAc(3×25 ml), dried (MgSO₄) and evaporated under reduced pressure. Theeresidue was purified by Flash chromatography (Merck 9385, EtOAc then 9:1EtOAc:MeOH) to give the title compound (0.279 g). LCMS RT=2.62 min.

ii)2-[3-(3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}phenyl)-2,5-dioxoimidazolidin-1-yl]acetamide

was prepared using methods similar to those described in Example 5iii).LCMS RT=3.27 min.

iii)2-[3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)-2,5-dioxoimidazolidin-1-yl]acetamide

was prepared using methods similar to those described in Example 5iv).LCMS RT=2.47 min.

iv)2-[3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-2,5-dioxoimidazolidin-1-yl]acetamide

was prepared using methods similar to those described in Example 5v).LCMS RT=2.56 min.

v)2-{3-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,5-dioxoimidazolidin-1-yl}acetamideacetate

was prepared using methods similar to those described in Example 1xii).LCMS RT=2.31 min, ES+ve 571 (MH)⁺.

EXAMPLE 281-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]imidazolidine-2,4-dioneacetate

i) Ethyl N-(3-iodobenzyl)glycinate

3-Iodobenzylamine hydrochloride (1.0 g) and diisopropylethylamine (1.29ml) were taken up in dry dimethylsulfoxide (60 ml) and treated withethyl bromoacetate and stirred under nitrogen for 2 h. 2M HCl (1.85 ml)and water (250 ml) were added. This was extracted with EtOAc, theaqueous phase was taken to pH 8 and extracted with EtOAc. The combinedextracts were dried (Na₂SO₄) and concentrated under reduced pressure.The residue was purified by chromatography (Biotage, 40 g) eluting withEtOAc-cyclohexane-diisopropylethylamine (10:89:1 then 20:79:1) to givethe title compound (0.571 g) LCMS RT 2.02 min.

ii) 1-(3-Iodobenzyl)imidazolidine-2,4-dione

Ethyl N-(3-iodobenzyl)glycinate (0.567 g) was treated with 1M HCl (3.9ml) and sodium cyanate (0.345 g) and then refluxed for 30 min.Concentrated HCl (4.5 ml) was added and the reaction mixture refluxedagain for 30 min. The reaction mixture was evaporated under reducedpressure and then triturated with EtOAc (3×20 ml). The combined extractswere dried (Na₂SO₄) and evaporated under reduced pressure to give thetitle compound (0.543 g). LCMS RT 2.63 min.

iii)1-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]benzyl}imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 3viii).LCMS RT=3.42 min.

iv)1-{3-[4-({6-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]benzyl}imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 3ix).LCMS RT=3.4 min.

v)1-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in example 3x).LCMS RT=2.6 min.

vi)1-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]imidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in example 1xii).LCMS RT=2.42 min, ES+ve 528 (MH)⁺.

EXAMPLE 291-Benzyl-3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

i) 1-Benzyl-3-(3-iodophenyl)imidazolidine-2,4-dione

A solution of 3-(3-iodophenyl)imidazolidine-2,4-dione (1.7 g) in DMF (20ml) was treated with sodium hydride (60% oil dispersion, 280 mg) andbenzylchloride (1.93 ml) at 20° C. After 2 h the reaction mixture wastreated with aqueous 2M HCl, extracted with EtOAc and dried (MgSO₄). Thesolvent was removed under reduced pressure and the residue was purifiedby chromatography on Biotage (40 g) eluting with petroleum ether-EtOAc(9:1 to 3:2) to give the title compound (1.38 g). LCMS RT=3.27 min.

ii)3-Benzyl-1-(3-{4-[(6-bromohexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iii.LCMS RT=3.90 min.

iii)1-Benzyl-3-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iv.LCMS RT=2.92 min.

iv)3-Benzyl-1-(3-{4-[(6-{[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5v.LCMS RT=2.72 min.

v)1-Benzyl-3-[3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dioneacetate

was prepared using methods similar to those described in Example 1xii.LCMS RT=2.67 min, ES+ve 604(MH)⁺.

EXAMPLE 303-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-1-(methylsulfonyl)imidazolidine-2,4-dioneacetate

i) 3-(3-Iodophenyl)-1-(methylsulfonyl)imidazolidine-2,4-dione

A solution of 3-(3-iodophenyl)imidazolidine-2,4-dione (950 mg) andN,N-diisopropylethylamine (1.1 ml) in DCM (20 ml) was treated withmethanesulfonyl chloride (0.453 ml) at 20° C. After 2 h the reactionmixture was diluted with DCM and washed with aqueous 2M HCl (3×20 ml)and NaHCO₃ and dried (MgSO₄). The solvent was removed under reducedpressure to give the title compound (1.15 g). LCMS RT=2.91 min.

ii)3-(3-{4-[(6-Bromohexyl)oxy]but-1-ynyl}phenyl)-1-(methylsulfonyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 5iii.LCMS RT=3.60 min.

iii)3-(3-{4-[(6-{Benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-4-yl)-2-hydroxyethyl]amino}hexyl)oxy]but-1-ynyl}phenyl-1-(methylsulfonyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 6i.LCMS RT=2.94 min.

iv)3-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-1-(methylsulfonyl)imidazolidine-2,4-dione

was prepared using methods similar to those described in Example 6ii.LCMS RT=2.72 min.

v)3-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-1-(methylsulfonyl)imidazolidine-24,-dione acetate

was prepared using methods similar to those described in Example 1xii.LCMS RT=2.48 min, ES+ve 592(MH)⁺.

EXAMPLE 314-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-1,2,4-triazolidine-3,5-dioneacetate

i) Ethyl 2-{[(3-iodophenyl)amino]carbonyl}hydrazinecarboxylate

A solution of ethyl carbazate (1.25 g) in dichloromethane (20 ml) wastreated with 3-iodophenylisocyanate (1.7 g) at 0° C. The reactionmixture was allowed to warm to 20° C. and stirred for 2 h. Ethanol (2ml) was added and the mixture was stirred for 0.5 h. The solvents wereremoved under reduced pressure and the residue was triturated in diethylether. The white solid was collected by filtration to give the titlecompound (2.4 g). LCMS RT=2.81 min

ii) Ethyl2-[({3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)but-1-ynyl]phenyl}amino)carbonyl]hydrazinecarboxylateWas prepared using methods similar to those described in Example 3viiiLCMS RT=3.46 min

iii) Ethyl2-[({3-[4-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)butyl]phenyl}amino)carbonyl]hydrazinecarboxylateWas prepared using methods similar to those described in Example 3ixLCMS RT=3.50 min

iv)4-(3-{4-[(6-{[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}phenyl)-1,2,4-triazolidine-3,5-dioneWas prepared using methods similar to those described in Example 3x LCMSRT=2.42 min

v)4-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-1,2,4-triazolidine-3,5-dioneacetate Was prepared using methods similar to those described in Example1xii LCMS RT=2 min, ES+ve 515 (MH)⁺

BIOLOGICAL ACTIVITY

The potencies of the aforementioned compounds were determined using frogmelanophores transfected with the human beta 2 adrenoreceptor. The cellswere incubated with melatonin to induce pigment aggregation. Pigmentdispersal was induced by compounds acting on the human beta 2adrenoreceptor. The beta 2 agonist activity of test compounds wasassessed by their ability to induce a change in light transmittanceacross a melanophore monolayer (a consequence of pigment dispersal). Atthe human beta 2 adrenoreceptor, compounds of examples 1–31 had IC₅₀values below 1 μM.

Potency at other beta adrenoreceptor subtypes was determined usingchinese hamster ovary cells transfected with either the human beta 1adrenoreceptor or the human beta 3 adrenoreceptor. Agonist activity wasassessed by measuring changes in intracellular cyclic AMP.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation, the following claims:

1. A compound of formula (I)

or a salt or solvate thereof, wherein: m is 5; n is 4; R¹ is —X—R⁶;wherein X is selected from —(CH₂)_(p)— and C₂₋₆alkenylene; R⁶ isselected from

R⁷ and R^(7a) are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C(O)R^(7b), C(O)NHR^(7b), phenyl, naphthyl, andphenyl(C₁₋₄alkyl)-, and R⁷ and R^(7a) are optionally substituted by 1 or2 groups independently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl), —SO₂(C₁₋₆alkyl), —SO₂(phenyl), —CO₂H,and —CO₂(C₁₋₄alkyl); R^(7b) is selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, and phenyl(C₁₋₄alkyl), and R^(7b) isoptionally substituted by 1 or 2 groups independently selected fromhalo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl),—SO₂(C₁₋₆alkyl), —SO₂(phenyl), —CO₂H, and —CO₂(C₁₋₄alkyl); R⁸, R^(8a),R⁹ and R^(9a) are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, phenyl(C₁₋₄alkyl)-, —NR^(10a)SO₂R¹⁰,—NR^(10a)C(O)NR¹⁰R¹¹, —SO₂NR¹⁰R¹¹, and C₁₋₆alkyl substituted by —CO₂R¹⁰or —C(O)NR¹⁰R¹¹; R¹⁰R^(10a) and R¹¹ are independently selected fromhydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, and phenyl (C₁₋₄alkyl)-; pis an integer from 0 to 6; R² is selected from hydrogen, C₁₋₆alkyl,C₁₋₆alkoxy, phenyl, halo, and C₁₋₆haloalkyl; R³ is selected fromhydrogen, hydroxyl, C₁₋₆alkyl, C₁₋₆alkoxy, phenyl, halo, C₁₋₆haloalkyl,—NR⁷CONR⁷R^(7a), and —SO₂NR^(a)R^(b); wherein R^(a) and R^(b) areindependently selected from hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl,and phenyl (C₁₋₄alkyl), or R^(a) and R^(b), together with the nitrogento which they are bonded, form a 5 membered nitrogen containing ring;and R^(a) and R^(b) are each optionally substituted by one or two groupsselected from halo, C₁₋₆alkyl, and C₁₋₆haloalkyl; and R⁴ and R⁵ areindependently selected from hydrogen and C₁₋₄alkyl with the proviso thatthe total number of carbon atoms in R⁴ and R⁵ is not more than
 4. 2. Acompound of formula (Ia)

wherein R¹ is —X—R⁶; wherein X is selected from —(CH₂)_(p)- andC₂₋₆alkenylene; R⁶ is selected from

R⁷ and R^(7a) are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C(O)R^(7b), C(O)NHR^(7b), phenyl, naphthyl, andphenyl(C₁₋₄alkyl)-, and R⁷ and R^(7a) are optionally substituted by 1 or2 groups independently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl), —SO₂(C₁₋₆alkyl), —SO₂(phenyl), —CO₂H,and —CO₂(C₁₋₄alkyl); R^(7b) is selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, and phenyl(C₁₋₄alkyl), and R^(7b) isoptionally substituted by 1 or 2 groups independently selected fromhalo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl),—SO₂(C₁₋₆alkyl), —SO₂(phenyl), —CO₂H, and —CO₂(C₁₋₄alkyl); R⁸, R^(8a),R⁹ and R^(9a) are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, phenyl(C₁₋₄alkyl)-, —NR^(10a)SO₂R¹⁰,—NR^(10a)C(O)NR¹⁰R¹¹, —SO₂NR¹⁰R¹¹, and C₁₋₆alkyl substituted by —CO₂R¹⁰or —C(O)NR¹⁰R¹¹; R¹⁰R^(10a) and R¹¹ are independently selected fromhydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, and phenyl (C₁₋₄alkyl)-; pis an integer from 0 to 6; or a salt or solvate thereof.
 3. A compoundof formula (Ib)

wherein R¹ is —X—R⁶; wherein X is selected from —(CH₂)_(p)- andC₂₋₆alkenylene; R⁶ is selected from

R⁷ and R^(7a) are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C(O)R^(7b), C(O)NHR^(7b), phenyl, naphthyl, andphenyl(C₁₋₄alkyl)-, and R⁷ and R^(7a) are optionally substituted by 1 or2 groups independently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl), —SO₂(C₁₋₆alkyl), —SO₂(phenyl), —CO₂H,and —CO₂(C₁₋₄alkyl); R^(7b) is selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, and phenyl(C₁₋₄alkyl), and R^(7b) isoptionally substituted by 1 or 2 groups independently selected fromhalo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl),—SO₂(C₁₋₆alkyl), —SO₂(phenyl), —CO₂H, and —CO₂(C₁₋₄alkyl); R⁸, R^(8a),R⁹ and R^(9a) are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, phenyl(C₁₋₄alkyl)-, —NR^(10a)SO₂R¹⁰,—NR^(10a)C(O)NR¹⁰R¹¹, —SO₂NR¹⁰R¹¹, and C₁₋₆alkyl substituted by —CO₂R¹⁰or —C(O)NR¹⁰R¹¹; R¹⁰R^(10a) and R¹¹ are independently selected fromhydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, and phenyl (C₁₋₄alkyl)-; pis an integer from 0 to 6; or a salt or solvate thereof.
 4. A compoundof formula (Ic):

wherein R¹ is —X—R⁶; wherein X is selected from —(CH₂)_(p)- andC₂₋₆alkenylene; R⁶ is selected from

R⁷ and R^(7a) are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C(O)R^(7b), C(O)NHR^(7b), phenyl, naphthyl, andphenyl(C₁₋₄alkyl)-, and R⁷ and R^(7a) are optionally substituted by 1 or2 groups independently selected from halo, C₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl), —SO₂(C₁₋₆alkyl), —SO₂(phenyl), —CO₂H,and —CO₂(C₁₋₄alkyl); R^(7b) is selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, and phenyl(C₁₋₄alkyl), and R^(7b) isoptionally substituted by 1 or 2 groups independently selected fromhalo, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆haloalkyl, —NHC(O)(C₁₋₆alkyl),—SO₂(C₁₋₆alkyl), —SO₂(phenyl), —CO₂H, and —CO₂(C₁₋₄alkyl); R⁸, R^(8a),R⁹ and R^(9a) are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, phenyl, naphthyl, phenyl(C₁₋₄alkyl)-, —NR^(10a)SO₂R¹⁰,—NR^(10a)C(O)NR¹⁰R¹¹, —SO₂NR¹⁰R¹¹, and C₁₋₆alkyl substituted by —CO₂R¹⁰or —C(O)NR¹⁰R¹¹; R¹⁰R^(10a) and R¹¹ are independently selected fromhydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, phenyl, and phenyl (C₁₋₄alkyl)-; pis an integer from 0 to 6; or a salt or solvate thereof.
 5. A compoundaccording to claim 1 or claim 2 selected from:3-[3-(4-{[6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;3-[3-(4-{[6-([(2S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;3-[3-(4-{[6-([(2R/S)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione;2-{3-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]-2,5-dioxoimidazolidin-1-yl}acetamide;andN-{1-[3-(4-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)benzyl]-2,5-dioxoimidazolidin-4-yl}urea;or a salt or solvate thereof.
 6. A compound according to claim 3 orclaim 4 which is3-[3-(5-{[6-({(2R)-2-Hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}pentyl)phenyl]imidazolidine-2,4-dioneor a salt or solvate thereof.
 7. A compound according to claim 1 whereinR⁶ is selected from one of the moieties (a)–(j).
 8. A method for thetreatment of a clinical condition in a mammal, for which a selectiveβ₂-adrenoreceptor agonist is indicated, wherein said clinical conditionis selected from the group consisting of asthma, chronic obstructivepulmonary diseases, respiratory tract infection, and upper respiratorytract disease, said method comprises administrating of a therapeuticallyeffective amount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt or solvate, thereof.
 9. Apharmaceutical formulation comprising a compound of formula (I)according to claim 1, or a pharmaceutically acceptable salt or solvatethereof, and a pharmaceutically acceptable carrier or excipient, andoptionally one or more other therapeutic ingredients.
 10. A process forthe preparation of a compound of formula (I), (Ia), (Ib) or (Ic)according to claim 1, or a salt or solvate thereof, wherein said processis selected from the group consisting of (a) through (e): (a)deprotection a protected intermediate of formula (II):

or a salt or solvate thereof, wherein R¹, R², R³, R⁴, R⁵, m, and n areas defined for the compound of formula (I) or (Ia), and R¹², R¹³ and R¹⁴are each independently either hydrogen or a protecting group providedthat at least one of R¹², R¹³, and R¹⁴ is a protecting group; (b)alkylation an amine of formula (XII)

wherein R¹², R¹³, R¹⁴ and R¹⁸ are each independently either hydrogen ora protecting group, with a compound of formula (XIII):

wherein R¹, R², R³, R⁴, R⁵, m, and n are as defined for the compound offormula (I) or (Ia) and L¹ is a leaving group; (c) reduction of acompound of formula (XIV):

wherein R¹, R², R³, R⁴, R⁵, m and n are as defined for formula (I) andR¹², R¹³, R¹⁴ and R¹⁸ each independently represent a hydrogen atom or aprotecting group as defined above; (d) reacting a compound of formula(XVIII):

wherein R¹² R¹³ and R¹⁸ are as hereinbefore defined and L⁴ is a leavinggroup, with an amine of formula (IX):

and (e) removal a chiral auxiliary from a compound of formula (IIa):

wherein R¹, R², R³, R⁴, R⁵, m and n are as defined for formula (I) andR¹², R¹³, R¹⁴ and R¹⁸ each independently represent a hydrogen atom or aprotecting group as defined above and R¹⁹ represents a chiral auxiliary;wherein any of (a) through (e) may optically be followed by one or moreselected from the group consisting of (i) through (iii) (i) removing anyprotecting groups; (ii) separating an enantiomer from a mixture ofenantiomers; and (iii) converting the product to a corresponding salt orsolvate thereof.
 11. A compound of formula (II) as defined in claim 10.12. A compound of formula (XIV) as defined in claim
 10. 13. A method forthe treatment of a clinical condition in a mammal, for which a selectiveβ₂-adrenoreceptor agonist is indicated, wherein said clinical conditionis selected from the group consisting of asthma, chronic obstructivepulmonary diseases, respiratory tract infection, and upper respiratorytract disease, said method comprises administering a therapeuticallyeffective amount of a compound of formula (Ia) according to claim 2, ora pharmaceutically acceptable salt or solvate thereof.
 14. Apharmaceutical formulation comprising a compound of formula (Ia)according to claim 2, or a pharmaceutically acceptable salt or solvatethereof, and a pharmaceutically acceptable carrier or excipient, andoptionally one or more other therapeutic ingredients.
 15. A method forthe treatment of a clinical condition in a mammal, for which a selectiveβ₂-adrenoreceptor agonist is indicated, wherein said clincal conditionis selected from the group consisting of asthma, chronic obstructivepulmonary diseases, respiratory tract infection, and upper respiratorytract disease, said method comprises administrating a therapeuticallyeffective amount of a compound of formula (Ib) according to claim 3, ora pharmaceutically acceptable salt or solvate thereof.
 16. Apharmaceutical formulation comprising a compound of formula (Ib)according to claim 3, or a pharmaceutically acceptable salt or solvatethereof, and a pharmaceutically acceptable carrier or excipient, andoptionally one or more other therapeutic ingredients.
 17. A method forthe treatment of a clinical condition in a mammal, for which a selectiveβ₂-adrenoreceptor agonist is indicated, wherein said clinical conditionis selected from the group consisting of asthma, chronic obstructivepulmonary diseases, respiratory tract infection, and upper respiratorytract disease, said method comprises administrating a therapeuticallyeffective amount of a compound of formula (I) according to claim 4, or apharmaceutically acceptable salt or solvate thereof.
 18. Apharmaceutical formulation comprising a compound of formula (Ic)according to claim 4, or a pharmaceutically acceptable salt or solvatethereof, and a pharmaceutically acceptable carrier or excipient, andoptionally one or more other therapeutic ingredients.
 19. A processaccording to claim 10, wherein R¹² and R¹³ together represent aprotecting group in the form of a compound of formula (III):

or a salt or solvate thereof, wherein R¹⁵ and R¹⁶ are each independentlyselected from the group consisting of hydrogen, C₁₋₆ alkyl, and aryl.20. A compound of formula (III) as defined in claim 19.